PR/SET-domain containing nucleic acids, polypeptides, antibodies and methods of use

ABSTRACT

The present invention provides an isolated nucleic acid molecule encoding a PFM/SET polypeptide. Also provided is an isolated nucleic acid molecule encoding a functional fragment of a PFM/SET polypeptide that contains a PR, SET, PRAZ or PKZL domain of a PFM/SET polypeptide of the invention. Further provided by the invention are PFM/SET polypeptides, and functional fragments thereof that contain a PR, SET, PRAZ or PKZL domain of a PFM/SET polypeptide. The invention also provides PFM/SET antibodies, PFM/SET modulatory compounds, and related methods. The molecules and methods of the invention can be used to modulate cell proliferation to prevent or treat proliferative disorders, including cancer. Additionally, the molecules and methods of the invention can be used to diagnose and prognose proliferative disorders.

[0001] This invention was made in part with government support undergrant number CA67146, awarded by the National Institutes of Health.Accordingly, the United States government has certain rights in thisinvention.

BACKGROUND OF THE INVENTION

[0002] 1Field of the Invention

[0003] This invention relates generally to proliferative disorders suchas cancer and, more specifically, to PR/SET-domain containing genes andgene products that can be used to diagnose and treat proliferativedisorders.

[0004] 2Background Information

[0005] Cancer is one of the leading causes of death in industrializednations. Cancerous tumors result when a cell escapes from its normalgrowth regulatory mechanisms and proliferates in an uncontrolledfashion. Cells from the primary tumor generally metastasize to vitalorgans if treatment of the primary tumor is either not complete or notinitiated early enough. Thus, early diagnosis and effective treatment oftumors is essential for survival.

[0006] Cancer involves the clonal replication of populations of cellsthat have gained competitive advantage over normal cells through thealteration of regulatory genes. Regulatory genes can be broadlyclassified into “oncogenes” which, when activated or overexpressedpromote unregulated cell proliferation, and “tumor suppressor genes”which, when inactivated or underexpressed fail to prevent abnormal cellproliferation. Loss of function or inactivation of tumor suppressorgenes is thought to play a central role in the initiation andprogression of a significant number of human cancers.

[0007] A number of tumor suppressor genes have been identified that,when inactivated, are involved in the initiation or progression of humancancers. Known tumor suppressor genes include RB, p53, DCC, APC/MCC,RIZ, NF1, NF2, WT1, VHL, BRCA1, MST1 and WAF1/CIP1. Approaches fortreating cancer by modulating the function of several of these tumorsuppressor genes, either with pharmaceutical compounds that target theirencoded proteins, or by gene therapy methods, have yielded promisingresults in animal models and in human clinical trials.

[0008] Approaches for diagnosing and prognosing cancer by identifyingmutations in tumor suppressor genes have also been developed. Forexample, identifying individuals containing germline mutations in knowntumor suppressor genes has permitted the identification of individualsat increased risk of developing cancer. Such individuals are thenclosely monitored or treated prophylactically to improve their chance ofsurvival. Identifying the pattern of alterations of known tumorsuppressor genes in biopsy samples is also being used to determine thepresence or stage of a tumor. Being able to determine whether a canceris benign or malignant, or at an early or late stage of progression,provides the patient and clinician with a more accurate prognosis andcan be used to determine and monitor the course of treatment.

[0009] One important family of tumor suppressor genes that has recentlybeen identified are PR/SET-domain containing genes. PR and SET domainsare structurally related motifs present in proteins that function inmodulating gene activities from yeast to mammals. A PR domain is a motiffirst identified as a region of homology between the Rb-binding zincfinger protein RIZ, and the transcriptional repressor proteinPRDI-BFI/Blimpl, which promotes B-cell differentiation (Buyse et al.,Proc. Natl. Acad. Sci. USA 92:4467-4471 (1995); Huang, Cell 78:9(1994)). A PR domain motif is also found in the MDS1-EVI1 myeloidleukemia gene (Fears et al., Proc. Natl. Acad. Sci. USA 93:1642-1647(1996)). A SET domain is a motif first identified as a region ofhomology between the Drosophila melanogaster genes Su(var)3-9,Enhancer-of-zeste and Trithorax. PR and SET domain-encoding genes havealso been identified in other mammals and in lower organisms, includingC. elegans, suggesting an evolutionarily conserved function for thesedomains.

[0010] In view of the importance of tumor suppressor genes and relatedmolecules in the detection and treatment of cancer, there exists a needto identify additional tumor suppressor genes. In particular, in view ofthe established role of PR/SET-domain containing genes as tumorsuppressor genes, there exists a need to identify and characterizeadditional PR/SET-domain family members. The present invention satisfiesthis need and provides related advantages as well.

SUMMARY OF THE INVENTION

[0011] The invention provides an isolated nucleic acid molecule encodinga PFM/SET polypeptide that has at least about 80% identity with an aminoacid sequence of an invention PFM/SET polypeptide.

[0012] The invention also provides an isolated nucleic acid moleculehaving a nucleotide sequence that encodes a functional fragment of aPFM/SET polypeptide, the functional fragment containing a PR, SET, PRAZ,or PKZL domain of a PFM/SET amino acid sequence of the invention.

[0013] Further provided is an isolated oligonucleotide containing atleast 17 contiguous nucleotides of an invention PFM/SET nucleotidesequence, or the complement thereof.

[0014] Also provided are methods for detecting a PFM/SET nucleic acidmolecule in a sample. In one embodiment, the method involves contactinga sample with the PFM/SET nucleic acid molecule under conditions thatallow specific hybridization to PFM/SET nucleic acid, and detecting saidspecific hybridization. In another embodiment, the method is practicedby contacting a sample with a PFM/SET primer pair under conditions thatallow amplification of PFM/SET nucleic acid, and detecting amplifiedPFM/SET nucleic acid.

[0015] Further provided is a method for modulating cell growth. Themethod involves introducing a vector containing an invention PFM/SETnucleic acid molecule into a host cell, and expressing encoded PFM/SETpolypeptide in an amount effective to modulate growth of said cell.

[0016] The invention also provides an isolated PFM/SET polypeptide,containing a PFM/SET amino acid sequence having at least about 80% aminoacid identity with an invention PFM/SET amino acid sequence.

[0017] Further provided by the invention is a functional fragment of aPFM/SET polypeptide, the functional fragment containing a PR, SET, PRAZ,or PKZL domain of a PFM/SET amino acid sequence of the invention

[0018] Also provided is an isolated immunogenic PFM/SET peptidecontaining at least 8 contiguous amino acids of an invention PFM/SETamino acid sequence.

[0019] The invention also provides an antibody, or antigen bindingfragment thereof, which specifically binds to a PFM/SET polypeptide ofthe invention.

[0020] Further provided is a method for detecting PFM/SET polypeptide ina sample. The method is practiced by contacting a sample with theantibody under conditions that allow specific binding of said antibodyto PFM/SET polypeptide, and detecting specifically bound antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]FIG. 1 shows a comparison of the amino acid sequences of the PRdomains of RIZ1 (SEQ ID NO:27), BLIMP1 (SEQ ID NO:28), MDS1-EVI1 (SEQ IDNO:29), HRX (ALL-1)(SEQ ID NO:30), and the SET domains of SET1 (SEQ IDNO:31), Su(var)3-9 (SEQ ID NO:32), and ASH1 (SEQ ID NO:33).

[0022]FIG. 2 shows the amino acid sequence of PFM6 (SEQ ID NO:2).Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0023]FIG. 3 shows the amino acid sequence of PFM7 (SEQ ID NO:4) .Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0024]FIG. 4 shows the amino acid sequence of PFM9 (SEQ ID NO:8) .Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0025]FIG. 5 shows the amino acid sequence of PFM10 (SEQ ID NO:10).Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0026]FIG. 6 shows the amino acid sequence of PFM11 (SEQ ID NO:12).Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0027]FIG. 7 shows the amino acid sequence of PFM12 (SEQ ID NO:14).Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0028]FIG. 8 shows the amino acid sequence of PFM13 (SEQ ID NO:16).Underlined sequences are the 5′ boundaries of each zinc finger motif.

[0029]FIG. 9 shows the amino acid sequence of PFM14 (SEQ ID NO:18).Underlined sequences are the 5′ boundaries of each zinc finger motif.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention provides “PFM/SET” nucleic acid molecules,polypeptides, antibodies, modulatory compounds, and related methods.“PFM/SET” nucleic acid molecules and polypeptides contain one or more“PR” or “SET” domains, which are structurally and functionally relatednucleotide and amino acid motifs. The PFM and SET nucleic acids andpolypeptides of the invention are important regulators of cellproliferation. Therefore, the molecules and methods of the invention canbe used to modulate cell proliferation so as to prevent or treatproliferative disorders, including cancer. Additionally, the moleculesand methods of the invention can be used to diagnose and prognoseproliferative disorders.

[0031] PFM/SET nucleic acid molecules and polypeptides are generallycharacterized by encoding or containing a PR domain or SET domain. ManyPFM/SET nucleic acid molecules and polypeptides also encode or contain azinc finger motif, and can contain other motifs. Exemplary PFM, or “PRfamily member” nucleic acid molecules include RIZ, MDS1-EVI1 andPRDI-BF1 (BLIMP1). Exemplary SET nucleic acid molecules includeHRX/ALL1/MLL and MMSET.

[0032] PR and SET domains have been demonstrated to be protein bindingmotifs involved in the regulation of gene expression (Huang et al., J.Biol. Chem. 273:15933-15940 (1998); Soderholm et al., Leukemia11:352-358 (1997)). In particular, the domains are considered tofunction in the assembly of chromatin-based multiprotein complexesinvolved in either euchromatin-mediated gene activation, orheterochromatin-mediated gene silencing. Lack or inactivation of the PRor SET domain can thus specifically inactivate the chromatin-associatedfunctions of a PFM/SET polypeptide, without affecting other activitiessuch as DNA binding and chromatin-independent transcriptional activationor repression. PFM genes encoding PR lacking isoforms of PFMpolypeptides have been characterized. Differential chromatin regulationby the PR+ and PR− forms of a PFM gene may underlie the opposite rolesof these products in tumorigenesis.

[0033] The PR domain is about 100 to 125 amino acids in length, andcontains three highly conserved sequences, designated the A, B and Cboxes, each of which consists of about 6 to 12 amino acids. Each ofboxes A, B and C is encoded by a separate exon. Alternative exon usageof the A, B and C boxes, and transcription from internal promoters, canresult in PFM transcripts and polypeptides containing all, some or noneof the A, B or C boxes.

[0034] Several observations indicate that PR-domain containing geneproducts are negative regulators of cell growth and tumorigenesis,whereas the PR-deficient products of these genes are involved in growthpromotion and oncogenesis. For example, the PR region of MDS1-EVI1 isoften disrupted by leukemia-associated chromosomal insertions andtranslocations. These disruptions result in loss of the PR-containingMDS1-EVI1 product and selective retention of the PR-deficient EVI1product. In contrast, the PR- EVI1 product is overexpressed in sometumor cells, and acts as an oncogene (Morishita et al., Cell 54:831-840(1988); Morishita et al., Proc. Natl. Acad. Sci. USA 89:3937-3941(1992))

[0035] Similarly, the RIZ gene produces two products, a PR-containingprotein, RIZ1, and a PR-deficient protein, RIZ2, which is generated froman internal promoter. RIZ1 is commonly absent or underexpressed in anumber of human neoplasias, including breast cancer, neuroblastoma andlung cancer. In these cases, the PR-deficient product, RIZ2, isexpressed at normal levels (He et al., Cancer Res. 58:4238-4244 (1998)).These results suggest that the PR-containing RIZ1 product is a negativeregulator of cell proliferation and tumorigenesis, whereas maintenanceof RIZ2 expression may be required for oncogenesis.

[0036] As further evidence that RIZ is a tumor suppressor gene, forcedexpression of the RIZ1 product in breast cancer cells causes cell cyclearrest at the G2/M phase of the cell cycle, and programmed cell death(He et al., Cancer Res. 58:4238-4244 (1998)). Additionally, consistentwith a role of RIZ1 in growth suppression, mice in which RIZ1, but notRIZ2, is inactivated, are tumor prone.

[0037] In addition, RIZ1 expression is commonly silenced in humancancers, including, for example, breast cancer, liver cancer, coloncancer, neuroblastoma, melanoma, lung cancer and osteosarcoma (He etal., supra (1998) and Jiang et al., Int. J. Cancer 83:541-547 (1999)).RIZ1 gene silencing occurs through methylation of CpG island motifscontained in the promotor region of the RIZ1 gene. RIZ1 deficiency inmice causes formation of B-cell lymphomas and other tumors, as well asaccelerated tumor formation in p53 mutant mice. In addition, frequentframe shift mutation of RIZ1 in colorectal tumors with DNA repairdefects have been observed (Chadwick et al., Proc. Natl. Acad. Sci. USA97:2662-2667 (2000), Piao et al., Cancer Res. 60:4701-4704 (2000), andSakurada et al., Genes, Chromosomes Cancer In press (2000))

[0038] Consistent with inactivation of RIZ1 in a broad spectrum of humancancers, recombinant adenovirus-mediated RIZ1 expression can induce G2/Mcell-cycle arrest, apoptosis, or both in several tumor cell lines(Chadwick et al., supra, (2000); He et al., supra (1998); Jiang et al.,supra, (1999)). RIZ1 can also suppress growth of xenograft colorectalcancers (Jiang and Huang, Histol Histopathol 15:109-117(2000)).

[0039] Another PR domain-containing gene, PRDI-BF1/BLIMP1 is also likelyto be a tumor suppressor gene. PRDI-BF1/BLIMP1 maps to the 6q21 regioncommonly deleted in non-Hodgkin's lymphoma (Mock et al., Genomics37:24-28 (1996)) and is thus a strong candidate tumor suppressor forB-cell non-Hodgkin's lymphoma. Additionally, PRDI-BF1/BLIMP1 is atranscriptional repressor of c-Myc (Lin et al., Science 276:596-598(1997)), which is an oncogene critically involved in B cell lymphoma.

[0040] The PR-domain containing gene PFM1/SC-1 is also likely to be atumor suppressor gene. PFM1/SC-1 localizes to a tumor suppressor locusand plays a role in promoting cell growth arrest and differentiationinduced by serum starvation and nerve growth factor (Chittka and Chao,Proc. Natl. Acad. Sci. USA, 96:10710-10750(1999); Yang and Huang,Genomics 61:319-325 (1999)).

[0041] SET nucleic acid molecules and polypeptides are characterized byencoding a “SET domain.” The SET domain is a 150 amino acid motifdiscovered to be contained in several Drosophila development genes(Jones and Gelbart, Mol. Cell Biol. 13:6357-6366 (1993); Tschiersch etal., EMBO J. 13:3822-3831 (1994)). SET stands for the names of threeDrosophila genes which contain the domain, Su(var)3-9, Enhancer-of-zesteand Trithorax. Other exemplary SET nucleic acid molecules include thehuman trithorax homolog HRX/ALL1/MLL, mutation of which has beenobserved in human leukemia (Djabali et al., Nature Genetics 2:113-118(1992; Gu et al., Cell 71:701-708 (1992); Tkachuk et al., Cell71:691-700 (1992)) and the MMSET gene, mutation of which has beenobserved in human myeloma (Chesi et al., Blood 92:3025-34 (1998).

[0042] Several SET domain containing genes in both Drosophila and mousefunction in maintaining gene expression (Yu et al., Proc. Natl. Acad.Sci. USA 95:10632-6 (1998)). In particular, several SET domaincontaining genes, members of the polycomb and trithorax groups ofDrosophila genes, function in sustaining homeobox gene expression bymaintaining genes in heterochromatin or euchromatin states (Yu et al.,supra, (1998)).

[0043] SET and PR domains are structurally and functionally related.These domains share amino acid identity in about 20% of amino acidresidues, typically among the most conserved residues in each domain(Huang et al., J. Biol. Chem. 273:15933-15940 (1998)). For example, oneof the two conserved leucine residues required for RIZ1 PR proteinbinding activity is also conserved in the SET domain (Huang et al.,supra,(1998)). FIG. 1 shows an amino acid sequence comparison of the PRdomains of RIZ1, BLIMP1, MDSa-EVI1, HRX (ALL-1) and the SET domains ofSET1, Su(var)3-9, and ASH1. The conserved residues among these domainsare highlighted.

[0044] Recent data suggest that PR and SET domains are functionallyrelated, both having protein methyltransferase activity that regulatesthe function of histones and other proteins, particularly during mitosis(Bannister et al., Nature 410:120-124 (2001); Lachner et al., Nature410:116-120 (2001); Rea et al., Nature 406:593-599 (2000)). PR/SETdomain containing genes have also been shown to function in cell memoryand in maintaining gene expression patterns in differentiated cellsthrough many cell divisions (Caldas and Aparicio, Cancer & MetastasisReviews 18:313-29 (1999)). In addition, a recent study in yeast suggestsa close relationship between the SET protein SETlp and the checkpointproteins Mec3p and Rad9p (Corda et al., Nature Genetics 21:204-8(1999)). The study suggests an important role of the PR/SET domainchromosomal proteins in linking checkpoint to DNA damage in the contextof chromatin.

[0045] The methyltransferase activity of PR/SET domains contributes tothe tumor suppressor function of polypeptides containing this domain.The observation that altered cellular methyltransferase activity isassociated with tumorigenesis supports an important role for themethyltransferase activity of PR and SET domains in PFM/SET polypeptidetumor suppressor function. For example, cancer cells commonly lose theenzyme methylthioadenosine phosphorylase (MTAP) (Toohey et al.,Biochemical and Biophysical Research Communications, 78:1273-1280(1977)). An inhibitor of methyltransferases, methylthioadenosine (MTA),commonly accumulates in cancer cells as a result of MTAP deficiency(Nobori, et al. Proc. Natl. Acad. Sci. USA, 93:6203-6208 (1996)). MTAinhibits the aminopropyltransferase enzymes that synthesize polyaminesfrom putrescine and decarboxylated S-adenosylmethionine, and alsoimpairs S-adenosylmethionine dependent trans-methylation reactions.

[0046] MTAP is abundant in normal tissues and prevents the inhibition bycleaving MTA to adenine and 5′-methylthioribose L-phosphate, that arerecycled to adenine nucleotides and methionine, respectively. MTAP is˜100 kb apart from the tumor suppressor p16INK4A (CDKN2) on chromosome9p21, one of the most commonly deleted (homozygous) regions in humancancer. Homozygous deletions at 9p21 commonly involve both genes in manycancers (Toohey et al., supra (1977)). MTAP deletion could facilitatetumor formation and/or progression by causing accumulation of the MTaseinhibitor, MTA, which in turn could inactivate RIZ1 and related PFM/SETfamily of tumor suppressor genes.

[0047] In addition to encoding proteins characterized by biologicalactivities consistent with tumor suppressor functions in cells, severalPR/SET domain-containing genes are localized to regions of humanchromosomes associated with a variety of cancers. Consistent with thisobservation, genomic sequences corresponding to the isolated PR/SETnucleic acids of the invention have been mapped to chromosomal regionsthat are altered in human cancers, as summarized in Table 1. The cancersindicated in Table 1 are abbreviated as follows: B-lym—B lymphocytes,Blad—bladder, Co—colon, Eso—esophagus, Fibr(+)—fibrosarcoma,Leu—leukemia, Li—liver, Lu—lung, Ma—mammary, Oral—oral tumor, Ov—ovary,Ov(+)—amplication, Ov(−)—deletion, Pr—prostate, Mel—melanoma,St—stomach, Nc—neurocrest tumor. TABLE 1 GENE CHROMOSOME CANCER PRDM16q21-q22.1 B-lym, (PRDIBF1/BLIMP1) Mel, St PRDM2 (RIZ1) 1p36.13-p36.23B-lym, Li, Ma, Co, St, Nc PRDM3 (MDS1-EVI1) 3q26 Leu (+/−), Ov (+) PRDM4(PFM1/SC1) 12q23-24.1 Pa, Ov, St PRDM5 (PFM2) 4q25-q26 Ov, Ma, Li, Lu,Co PRDM6 (PFM3) 5q21-q23 Co, Lu, Ov St, Leu PRDM7 (PFM4) 16q24 Ma, Pr,Li PRDM8 (PFM5) 4q21.1 Co PRDM9 (PFM6) 5p14 Ov (+), fibr. (+) PRDM10(PFM7) 11q25 Ma, Co, Ov Oral PRDM11 (PFM8) 11p11.2 Ma PRDM12 (PFM9)9q33-q34.1 Ov, Blad, Eso, lu PRDM13 (PFM10) 6q16-q21 B-lym, Mel, StPRDM14 (PFM11) 8p12-21 Ma, Pr PRDM15 (PFM12) 21q22.3 Leu, Blad PRDM16(PFM13) 1p36.23-p36.33 B-lym, Li, Ma, Co, St, Nc SET07 13q11-q13 Ma

[0048] The PFM/SET nucleic acid molecules and encoded polypeptides ofthe invention can additionally contain a zinc finger domain, or “ZFdomain.” Generally, the ZF domain contains one or several C2H2 orKrüppel-like Zinc finger motifs, which can be represented by thestructure: Cys-X2-Cys-X12-His-X3-His. However, a zinc finger motif of aPFM/SET polypeptide can have an amino acid other than Cys or His at oneor more of the four conserved positions, and/or alternative spacingsbetween the four conserved positions. The zinc finger motif is found inat least 300 human genes, and is known to specifically bind DNA or RNAsequences (Bellefroid et al., DNA 8:377-387 (1989)).

[0049] The PFM/SET nucleic acid molecules of the invention can containone or more individual zinc finger motifs within a zinc finger domain.For example, PFM6 contains 14 individual zinc finger motifs within thezinc finger domain, while PFM7, PFM13 and PFM14 contain 10 zinc fingermotifs, and PFM9, PFM10 and PFM12 contain 3, 4, and 8 zinc fingermotifs, respectively.

[0050] The zinc finger motifs within the PFM/SET nucleic acid moleculesand polypeptides of the invention can be contained in one or more zincfinger domains. For example, the 10 zinc finger motifs of PFM7 arecontained in a single zinc finger domain (amino acids 271-752) while the10 zinc finger motifs of PFM13 are contained in two separate zinc fingerdomains (amino acids 149-169 and 585-682). The individual zinc fingermotifs of each invention PFM/SET polypeptide are depicted in FIGS. 2through 11, which show the amino acid sequences of PFM6, PFM7, PFM9,PFM10, PFM11, PFM12, PFM13, PMF14, and SET07, respectively. Zinc fingermotifs are identified by underlining.

[0051] PFM/SET nucleic acid molecules and encoded polypeptides canadditionally contain a variety of other motifs, including, for example,acidic motifs, PKZL domains and PRAZ domains, as described below foreach PFM/SET nucleic acid molecule of the invention.

[0052] The PFM/SET nucleic acid molecules and polypeptides of theinvention are designated PFM6, PFM7, PFM8, PFM9, PFM10, PFM11, PFM12,PFM13, PFM14 and SET07. The nucleotide sequences of these PFM nucleicacid molecules are set forth as SEQ ID NO:1 (PFM6); SEQ ID NO:3 (PFM7);SEQ ID NO:5 (PFM8); SEQ ID NO:7 (PFM9); SEQ ID NO:9 (PFM10); SEQ IDNO:11 (PFM11); SEQ ID NO:13 (PFM12); SEQ ID NO:15 (PFM13), SEQ ID NO:17(PFM14) and SEQ ID NO:19 (SET07). The amino acid sequences of theencoded PFM polypeptides are set forth as SEQ ID NO:2 (PFM6); SEQ IDNO:4 (PFM7); SEQ ID NO:6 (PFM8); SEQ ID NO:8 (PFM9); SEQ ID NO:10(PFM10); SEQ ID NO:12 (PFM11); SEQ ID NO:14 (PFM12); SEQ ID NO:16(PFM13), SEQ ID NO:18 (PFM14) and SEQ ID NO:10 (SET07).

[0053] The amino acid boundaries of the PR and ZF domains of PFM6, PFM7,PFM8, PFM9, PFM10, PFM11, PFM12, PFM13 and PFM14 are provided in Table2, below. TABLE 2 PR domain ZF domain amino acid amino acid PFM moleculeresidues residues PFM6  1-160 335-690 PFM7 116-258 271-753 PFM8 128-165not present PFM9  84-217 245-333 PFM10  1-131 149-169, 585-682 PFM11252-292 402-566 PFM12 414-539 248-277, 565-951 PFM13  93-218 219-448,915-1030 PFM14  45-182 355-624

[0054] PFM6 additionally contains a domain of approximately 100 aminoacids having about 35-40% identity to the KRAB-domain-containing zincfinger protein 133 (ZNF133). This domain is designated PKZL, for “PR andKRAB zinc finger protein-linked.” The PKZL domain of PFM6 corresponds toamino acids 211-310 of SEQ ID NO:2. The PKZL domain likely is importantin mediating protein-protein interactions with cellular regulatorymolecules.

[0055] PFM7, PFM8 and PFM12 additionally contain a PRAZ domain. PFM6contains a partial PRAZ domain at the N-terminus. PRAZ stands forPR-domain Associated Zinc Finger motif. The signature sequence of thePRAZ domain is CX₂CX₇CX₂H/L. The PRAZ domain is typically located 5′ tothe PR domain in PFM polypeptide sequences, and has thus far beenidentified only in PFM polypeptides. The PRAZ domain participates in themethyltransferase activity function of the PR domain. The PRAZ domain ofPFM6 corresponds to amino acids 1-13 of SEQ ID NO:2. The PRAZ domain ofPFM7 corresponds to amino acids 87-108 of SEQ ID NO:4. The PRAZ domainof PFM8 corresponds to amino acids 103-117 of SEQ ID NO:6. The PRAZdomain of PFM12 corresponds to amino acids 313-328 of SEQ ID NO:14.

[0056] The SET07 polypeptide of the invention contains a single SETdomain. The SET domain of SET07 corresponds to amino acids 215-334 ofSEQ ID NO:20.

[0057] The PFM and SET genes disclosed herein are localized to regionsof human chromosomes predicted to harbor tumor suppressor genes, becausedeletion of these regions is closely associated with various humantumors. In particular, PFM6 localizes to chromosome band 5p14, a regioncommonly rearranged or gained in ovarian and breast cancer (Sonoda etal. Genes, Chromosomes & Cancer 20(4):320-8, (1997)).

[0058] PFM7 localizes to chromosome band 11q25, a region commonlydeleted in breast, ovary, colon and oral cancer (Connolly et al., CancerResearch 59:2806-2809 (1999); Koreth et al., Oncogene 14:431-437 (1997);Launonen et al., Genecologic Oncoloqy 71:299-304 (1998); Uzawa et al.,Intl. J. Cancer 67:510-4 (1996)). It has also been demonstrated thatllq25 YAC clones can suppress tumor growth in vivo (Koreth et al.,Oncogene 18:1157-64 (1999)).

[0059] PFM8 localizes to chromosome band 11p11. This region ofchromosome 11 is commonly deleted in breast cancer (Nakata et al.,European J. Cancer 34:417-21 (1998)).

[0060] PFM9 localizes to chromosome band chromosome 9q33-34.1, which iscommonly deleted in ovarian, bladder, esophageal, and lung cancers(Devlin et al., British J. Cancer 73:420-423 (1996); Hornigold et al.,Oncogene 18:2657-61 (1999); Simoneau et al., Oncogene 18:157-63 (1999)).

[0061] PFM10 localizes to chromosome band 6q16-21, a region commonlydeleted in B-cell lymphoma, melanoma, and stomach cancers (Gaidano etal. Curr. Opin. Oncol. 5:778-784 (1993), Millikin et al. Cancer Res.51:5449- 5453 (1991), Trent et al. Cytogenet. Cell Genet. 62:67- 87(1990), and Queimado et al. Genes Chromosomes Cancer 14:28-34(1995)).This region also contains another PR-family member, the candidate tumorsuppressor PRDIBF1/BLIMP1 (PRDM1) (Mock et al., Genomics 37:24-28(1996)).

[0062] PFM11 localizes to chromosome band 8p12-21, a region commonlydeleted in breast and prostate cancers (Van Alewijk et al., Genes,Chromosomes & Cancer 24:119-26 (1999); Verma et al., CancerInvestigation 17:441-7 (1999); Vocke et al., Cancer Research 56:2411-6(1996)).

[0063] PFM12 localizes to chromosome band 21q22.3. This region is foundto be deleted in human leukemia.

[0064] PFM13 localizes to chromosome band 1p36.23-33, a region deletedin more than a dozen different types of human cancers. This region alsocontains other PR-family members, the tumor suppressors MDS1-EVI1 andRIZ1. These observations are consistent with a role for these PFMs astumor suppressors.

[0065] SET07 localizes to chromosome band 13q11-q13, in proximity to theretinoblastoma locus on 13q14. This region is commonly deleted in manycancers including breast cancers, bladder cancers, lung cancers andosteosarcomas.

[0066] PFM/SET nucleic acid molecules

[0067] The invention provides isolated PFM/SET nucleic acid molecules.The isolated PFM/SET nucleic acid molecules of the invention can be usedin a variety of diagnostic and therapeutic applications. For example, asdescribed in more detail below, the isolated PFM/SET nucleic acidmolecules of the invention can be used as probes and primers to detectPFM and SET nucleic acid molecules in samples; as templates for therecombinant expression of PFM and SET polypeptides; in two-hybrid assaysto identify cellular molecules that bind PFM and SET; and in vivo and exvivo gene therapy applications to positively or negatively modulate cellproliferation.

[0068] In one embodiment, the invention provides an isolated PFM/SETnucleic acid molecule encoding a PFM/SET polypeptide selected from thegroup consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and 20.Modifications of these sequences that having at least 80% identitythereto are also provided. Such modifications can have at least 90%, 95%and 98% identity with a reference PFM/SET nucleotide sequence.

[0069] Exemplary isolated PFM/SET nucleic acid molecules provided by theinvention are nucleic acid molecules having the sequence of SEQ IDNOS:1, 3, 5, 7, 8, 11, 13, 15, 17, or 19.

[0070] The invention also provides an isolated nucleic acid moleculecontaining a nucleotide sequence encoding a functional fragment of aPFM/SET polypeptide, said fragment comprising a PR, SET, PRAZ, or PKZLdomain of a PFM/SET amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and 20.

[0071] The term “isolated,” in reference to a PFM/SET nucleic acidmolecule is intended to mean that the molecule is substantially removedor separated from components with which it is naturally associated, orotherwise modified by the hand of man. Thus, the term “isolated PFM/SETnucleic acid molecule” excludes PFM/SET nucleic acid molecules as theyexist in nature.

[0072] The term “nucleic acid molecule,” as used herein, refers to anoligonucleotide or polynucleotide of natural or synthetic origin. Anucleic acid molecule can be single- or double-stranded genomic DNA,cDNA or RNA, and can represent the sense strand, the antisense strand,or both.

[0073] Identity of any two nucleic acid sequences can be determined bythose skilled in the art based, for example, on a BLAST 2.0 computeralignment. BLAST 2.0 searching is available at the National Institutesof Health web site (www.ncbi.nlm.nih.gov), and is described in Tatusovaet al., FEMS Microbiol Lett. 174:247-250 (1999).

[0074] A “modification” of a reference nucleic acid sequence can includeone or several nucleotide additions, deletions, or substitutions withrespect to the recited sequence. Such modifications can correspond tovariations that are made deliberately, or which occur as mutationsduring nucleic acid replication.

[0075] Exemplary “modifications” of the recited PFM/SET sequencesinclude sequences that correspond to homologs of other species, such asprimates, mouse, rat, rabbit, bovine, porcine, ovine, canine or felinespecies. The sequences of corresponding PFM/SET polypeptides ofnon-human species can be determined by methods known in the art, such asby PCR or by screening genomic, cDNA or expression libraries.

[0076] Furthermore, exemplary “modifications” of the recited PFM/SETnucleic acid or polypeptide can correspond to splice variant forms ofrecited PFM/SET sequences. Thus, for example, a modification of a PFMnucleic acid molecule of the invention can lack one or more of the exonsthat encode the A, B or C boxes of the PR domain. A, B, and C boxes of aPR domain can be determined by alignment of PR domain nucleotidesequences with known PR domain A, B, and C box sequences, or bycomparing the sequence of a PFM/SET cDNA to the sequence of thecorresponding genomic DNA. Exon usage by splice variants of PFM/SETnucleic acid molecules can be readily determined by those skilled in theart by comparing the sequence of the PFM/SET cDNA to the sequence of thecorresponding PFM/SET genomic DNA.

[0077] Additionally, a “modification” of a reference sequence caninclude one or more non-native nucleotides, having, for example,modifications to the base, the sugar, or the phosphate portion, orhaving a modified phosphodiester linkage. Such modifications can beadvantageous in increasing the stability of the nucleic acid molecule.

[0078] Furthermore, a “modification” of a reference sequence caninclude, for example, a detectable moiety, such as a radiolabel, afluorochrome, a ferromagnetic substance, a luminescent tag or adetectable binding agent such as biotin. Such modifications can beadvantageous in applications where detection of a PFM nucleic acidmolecule is desired.

[0079] Nucleic acid molecules having nucleic acid sequences that encodemodified polypeptides that are immunologically equivalent to the recitedPFM amino acid sequences are also provided.

[0080] The term “isolated PFM/SET nucleic acid molecule” specificallyexcludes nucleic acid molecules consisting of certain nucleotidesequences, such as Expressed Sequence Tags (ESTs), Sequence Tagged Sites(STSs) and genomic fragments, deposited in public databases such as thenr, dbest, dbsts, gss and htgs databases, which are available forsearching at http://www.ncbi.nlm.nih.gov/blast/blast.cgi?Jform=0, usingthe program BLASTN 2.0.9 [May 07, 1999] described by Altschul et al.,Nucleic Acids Res. 25:3389-3402 (1997).

[0081] In particular, the term “PFM/SET nucleic acid molecule”specifically excludes nucleic acid molecules consisting of any of thenucleotide sequences having the GenBank (gb), EMBL (emb) or DDBJ (dbj)Accession numbers set forth in Table 3, below: TABLE 3 PFM nucleicAccession Number of Excluded acid Sequence PFM6 gb|AC010432.6gb|AF274348.1 gb|AC025451.5 emb|AL137711 gb|AF274347.1 emb|Z96314 PFM7dbj|AB033057 gb|BE962422.1 dbj|AK000234 gb|BE994100.1 gb|AA324539.1gb|BF333514.1 gb|AA331245.1 gb|BF693866.1 gb|AA807222.1 gb|BG498843.1gb|AI348386.1 gb|G05930.1 gb|AI610587.1 gb|G20316.1 gb|AT699177.1gb|N32595.1 gb|AI907429.1 gb|R14616.1 gb|AI917820.1 gb|R15777.1gb|AW027068.1 gb|R16283.1 gb|AW131841.1 gb|R35195.1 gb|AW274834.1gb|R42665.1 gb|AW978331.1 gb|R45605.1 gb|AW992560.1 gb|R50855.1gb|BE304522.1 gb|T16683.1 gb|BE617458.1 PFM8 gb|AA468023.1 gb|BE884008.1gb|AA468074.1 gb|BE956829.1 gb|AC013602.4 gb|BE980340.1 gb|AW968153.1gb|D59353.1 gb|BE648497.1 PFM9 gb|AW529888.1 gb|BE096442.1 gb|AW532948.1gb|BE096447.1 gb|BE096110.1 gb|BE294489.1 gb|BE096155.1 gi|13274746PFM10 emb|AL137784.14 emb|AL035087.20 PFM11 dbj|AK022595.1 gb|BF770200dbj|AU124563 gb|G51347.1 dbj|AU148392 gi|13375633 emb|Z65361.1 PFM12djb|AP001618.1 gb|AW501914.1 djb|AP001619.1 gb|AW503893.1 djb|AP001745.1gb|AW968839.1 gb|AA279563.1 gb|BF904312.1 gb|AA490433.1 PFM13dbj|AB051462.1 gb|BG086572.1 dbj|AK017846.1 gi|13628859 gb|BF982577.1PFM14 dbj|AU130916 gb|BE793683.1 emb|AL535257 gb|BE798564.1 emb|AL565845gb|BE870276.1 gb|AA635466.1 gb|BE883835.1 gb|AA639997.1 gb|BF061011.1gb|AA759024.1 gb|BF182733.1 gb|AI092401.1 gb|BF346948.1 gb|AI242496.1gb|BF529537.1 gb|AI357201.1 gb|BF685622.1 gb|AI816535.1 gb|BF814715.1gb|AU128198.1 gb|BG177268.1 gb|AU147298.1 gb|BG470196.1 gb|AU152780.1gb|BG481345.1 gb|AW129728.1 gb|BG678255.1 gb|AW157409.1 gb|BG745296.1gb|AW245524.1 gb|BG746115.1 gb|AW245967.1 gb|BG753045.1 gb|AW246726.1gb|BG753749.1 gb|AW273736.1 gb|BG822286.1 gb|BE244872.1 gb|BG914332.1gb|BE246083.1 gb|BI116711.1 gb|BE247252.1 gb|BI117664.1 gb|BE732157.1gb|H63042.1 gb|BE744525.1 gb|H85444.1 gb|BE791132.1 gb|AI887341.1gb|BE897305.1 gb|AW163472.1 gb|H85725.1 gb|BE048089.1 gb|R37802.1gb|BE266801.1 gb|BE867579.1 SET07 dbj|AV752467 gb|BE018920.1emb|AL120271.1 gb|BE074968.1 emb|AL548156.1 gb|BE074969.1 emb|AL555671gb|BE074974.1 emb|AL578116 gb|BE305526.1 gb|912371.1 gb|BE536337.1gb|AA085455.1 gb|BE797607.1 gb|AA509936.1 gb|BE896201.1 9b|AA936703.1gb|BF133687.1 gb|AI002388.1 gb|BF161282.1 gb|AI383837.1 gb|BF245288.1gb|AI879547.1 gb|BF309152.1 gb|AV705547.1 gb|BG196219.1 gb|AW430084.1gb|BG311741.1 gb|AW986692.1 gb|BG389847.1 gb|BE014950.1 gb|BG922564.1gb|BI021983.1 gb|W72745.1

[0082] The invention also provides isolated PFM Oligonucleotidescontaining at least 17 contiguous nucleotides of PFM6, PFM7, PFM8, PFM9,PFM10, PFM11, PFM12, PFM13, PFM14 or SET07. As used herein, the term“oligonucleotide” refers to a nucleic acid molecule that includes atleast 17 contiguous nucleotides from the reference nucleotide sequence,can include at least 16, 17, 18, 19, 20 or at least 25 contiguousnucleotides, and often includes at least 30, 40, 50, 60, 70, 80, 90,100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 450, 550, 650,750, 850, 950 or more contiguous nucleotides from the referencenucleotide sequence. Therefore, an oligonucleotide can include theentire nucleotide sequence encoding a PFM/SET polypeptide. Anoligonucleotide can further contain an exogenous nucleotide sequence.Such exogenous nucleotide sequence includes, for example, a nucleotidesequence that facilitates identification or purification of theoligonucleotide, a nucleotide sequence that facilitates cloning, such asa sequence containing a restriction endonuclease recognition site, orany other nucleotide sequence not contained in a naturally occurringreference PFM/SET nucleotide sequence. Excluded from the nucleotidesequence of an invention PFM/SET oligonucleotide is non-coding sequenceadjacent to a naturally occurring PFM/SET nucleotide sequence, such asnucleotide sequence contained upstream or downstream of a naturallyoccurring PFM/SET nucleotide sequence, or portion thereof, in genomic orcDNA.

[0083] The PFM/SET oligonucleotides of the invention contain at least 17contiguous nucleotides from the reference PFM or SET nucleotide sequenceand are able to hybridize to PFM or SET nucleotide sequences undermoderately stringent hybridization conditions. Therefore, PFM/SEToligonucleotides can be advantageously used, for example, as probes todetect PFM or SET DNA or RNA in a sample, and to detect splice variantsthereof that contain or lack particular domains; as sequencing or PCRprimers; as antisense reagents to block transcription of PFM or SET RNAin cells; or in other applications known to those skilled in the art inwhich hybridization to a PFM or SET is desirable.

[0084] Oligonucleotides containing at least 17 contiguous PFM/SETnucleotides are able to specifically hybridize with a PFM or SET nucleicacid molecule. Specific hybridization refers to the ability of a nucleicacid molecule to hybridize, under moderately stringent conditions asdescribed above, to the reference PFM or SET nucleic acid molecule,without hybridization under the same conditions with nucleic acidmolecules that are not PFMs or SETs, respectively, such as actin cDNA.

[0085] Moderately stringent hybridization conditions refers tohybridization conditions that permit a nucleic acid molecule to bind anucleic acid that has substantial identity to the recited sequence.Moderately stringent conditions are conditions equivalent tohybridization of filter-bound nucleic acid in 50% formamide, 5×Denhart'ssolution, 5×SSPE, 0.2% SDS at 42° C., followed by washing in 0.2×SSPE,0.2% SDS, at 50°. In contrast, “highly stringent conditions” areconditions equivalent to hybridization of filter-bound nucleic acid in50% formamide, 5×Denhart's solution, 5×SSPE, 0.2% SDS at 42° C.,followed by washing in 0.2×SSPE, 0.2% SDS, at 65°. Other suitablemoderately stringent and highly stringent hybridization buffers andconditions are well known to those of skill in the art and aredescribed, for example, in Sambrook et al., Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory, New York (1992) and inAnsubel et al., Current Protocols in Molecular Biology, John Wiley andSons, Baltimore, Md. (1998).

[0086] In general, a nucleic acid molecule that hybridizes to a recitedsequence under moderately stringent conditions will have greater thanabout 60% identity, such as greater than about 70% identity, preferablygreater than about 80% identity to the reference sequence over thelength of the two sequences being compared. A nucleic acid molecule thathybridizes to a recited sequence under highly stringent conditions willgenerally have greater than about 90% identity, including greater thanabout 95% and 98% identity, to the reference sequence over the length ofthe two sequences being compared.

[0087] In one embodiment, the invention provides a primer pair fordetecting a PFM or SET nucleic acid. The primer pair contains twoPFM/SET oligonucleotides. The primer pair can be used, for example, toamplify PFM/SET DNA by RT-PCR or PCR.

[0088] The isolated PFM/SET nucleic acid molecules and oligonucleotidesof the invention can be produced or isolated by methods known in theart. The method chosen will depend, for example, on the type of nucleicacid molecule one intends to isolate. Those skilled in the art, based onknowledge of the nucleotide sequences disclosed herein, can readilyisolate PFM/SET nucleic acid molecules as genomic DNA, or desiredintrons, exons or regulatory sequences therefrom; as full-length cDNA ordesired fragments therefrom; or as full-length mRNA or desired fragmentstherefrom, by methods known in the art.

[0089] One useful method for producing an isolated PFM/SET nucleic acidmolecule of the invention involves amplification of the nucleic acidmolecule using the polymerase chain reaction (PCR) and PFM- orSET-specific primers and, optionally, purification of the resultingproduct by gel electrophoresis. Either PCR or reverse-transcription PCR(RT-PCR) can be used to produce a PFM nucleic acid molecule having anydesired nucleotide boundaries. Desired modifications to the nucleic acidsequence can also be introduced by choosing an appropriate primer withone or more additions, deletions or substitutions. Such nucleic acidmolecules can be amplified exponentially starting from as little as asingle gene or mRNA copy, from any cell, tissue or species of interest.

[0090] A further method of producing an isolated PFM/SET nucleic acidmolecule of the invention is by screening a library, such as a genomiclibrary, cDNA library or expression library, with a detectable agent.Such libraries are commercially available or can be produced from anydesired tissue, cell, or species of interest using methods known in theart. For example, a cDNA or genomic library can be screened byhybridization with a detectably labeled nucleic acid molecule having anucleotide sequence disclosed herein. Additionally, an expressionlibrary can be screened with an antibody raised against a polypeptidecorresponding to the coding sequence of a PFM/SET nucleic acid disclosedherein. The library clones containing PFM molecules of the invention canbe isolated from other clones by methods known in the art and, ifdesired, fragments therefrom can be isolated by restriction enzymedigestion and gel electrophoresis.

[0091] Furthermore, isolated PFM/SET nucleic acid molecules andoligonucleotides of the invention can be produced by synthetic means.For example, a single strand of a nucleic acid molecule can bechemically synthesized in one piece, or in several pieces, by automatedsynthesis methods known in the art. The complementary strand canlikewise be synthesized in one or more pieces, and a double-strandedmolecule made by annealing the complementary strands. Direct synthesisis particularly advantageous for producing relatively short molecules,such as oligonucleotide probes and primers, and nucleic acid moleculescontaining modified nucleotides or linkages.

[0092] The invention also provides a vector containing an isolatedPFM/SET nucleic acid molecule. The vectors of the invention are usefulfor subcloning and amplifying an isolated PFM/SET nucleic acid molecule,and for recombinantly expressing a PFM/SET polypeptide. A vector of theinvention can include a variety of elements useful for cloning and/orexpression of PFM/SET nucleic acid molecules, such as enhancer sequencesand promoter sequences from a viral, bacterial or mammalian gene, whichprovide for constitutive, inducible or cell-specific RNA transcription;transcription termination and RNA processing signals, includingpolyadenylation signals, which provide for stability of a transcribedmRNA sequence; an origin of replication, which allows for properepisomal replication; selectable marker genes, such as a neomycin orhygromycin resistance gene, useful for selecting stable or transienttransfectants in mammalian cells, or an ampicillin resistance gene,useful for selecting transformants in prokaryotic cells; and versatilemultiple cloning sites for inserting nucleic acid molecules of interest.

[0093] Cloning vectors of the invention include, for example, viralvectors such as a bacteriophage, a baculovirus or a retrovirus; cosmidsor plasmids; and, particularly for cloning large nucleic acid molecules,bacterial artificial chromosome vectors (BACs) and yeast artificialchromosome vectors (YACs). Such vectors are commercially available, andtheir uses are well known in the art.

[0094] If it is desired to express PFM/SET RNA transcripts orpolypeptides, a PFM/SET nucleic acid molecule can be inserted into anexpression vector such that it is operatively linked to a promoter ofRNA transcription. The term “operatively linked,” as used herein, isintended to mean that the nucleic acid molecule is positioned withrespect to a PFM/SET promoter, or heterologous promoter, in such amanner that the promoter will direct the transcription of RNA using thenucleic acid molecule as a template. Methods for operatively linking anucleic acid to a desired promoter are well known in the art andinclude, for example, cloning the nucleic acid into a vector containingthe desired promoter, or appending the promoter to a nucleic acidsequence using PCR. Thus, an expression vector containing a PFM/SETnucleic acid molecule operatively linked to a promoter of RNAtranscription can be used to express PFM/SET transcripts andpolypeptides in a desired host cell, or in an in vitro system, such asan extract or lysate that supports transcription and translation.Contemplated expression vectors include vectors containing regulatorysequences known in the art to provide for expression in bacterial cells,yeast cells, insect cells, mammalian cells and other vertebrate cells.

[0095] A variety of expression vectors are commercially available, andcan be further modified, if desired, to include appropriate regulatoryelements to provide for the desired level of expression or replicationin the host cell. For example, appropriate promoter and enhancerelements can be chosen to provide for constitutive, inducible or celltype-specific expression. Useful constitutive promoter and enhancerelements for expression of PFM/SET in mammalian cells include, forexample, RSV, CMV, SV40 and IgH elements. An exemplary inducibleexpression element is a steroid response element, while an exemplarycell-specific expression element is a prostate specific antigen (PSA)regulatory sequence. Other constitutive, inducible and celltype-specific regulatory elements are well known in the art.

[0096] Exemplary host cells that can be used to express recombinantPFM/SET molecules include mammalian primary cells; established mammaliancell lines, such as COS, CHO, HeLa, NIH3T3, HEK 293-T and PC12 cells;amphibian cells, such as Xenopus embryos and oocytes; and othervertebrate cells. Exemplary host cells also include insect cells (e.g.Drosophila), yeast cells (e.g. S. cerevisiae, S. pombe, or Pichiapastoris) and prokaryotic cells (e.g. E. coli).

[0097] Methods for introducing a cloning or expression vector into ahost cell are well known in the art and include, for example, variousmethods of transfection such as calcium phosphate, DEAE-dextran andlipofection methods, viral transduction, electroporation andmicroinjection. Host cells expressing PFM or SET nucleic acid moleculescan be used, for example, as a source to isolate recombinantly expressedPFM or SET polypeptides, to identify and isolate molecules that regulateor interact with PFM/SET nucleic acids and polypeptides, or to screenfor compounds that enhance or inhibit the activity of a PFM/SET moleculeof the invention, as described further below.

[0098] The methods of isolating, cloning and expressing nucleic acidmolecules of the invention referred to herein are routine in the art andare described in detail, for example, in Sambrook et al., MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York(1992) and in Ansubel et al., Current Protocols in Molecular Biology,John Wiley and Sons, Baltimore, Md. (1998), which are incorporatedherein by reference.

[0099] PFM/SET polypeptides

[0100] The invention also provides isolated PFM/SET polypeptides. Asdisclosed herein, PFM and SET domains are similar in both amino acidsequence and in biological function. As such, a PFM and SET domains aremembers of a class of domains, referred to herein as PFM/SET domains.The isolated PFM/SET nucleic acid molecules and polypeptides of theinvention contain either a PFM or SET domain. The isolated PFM and SETpolypeptides of the invention can be used in a variety of diagnostic andtherapeutic applications. For example, as described in more detailbelow, the isolated PFM/SET polypeptides can be used to generateantibodies that can be used as reagents to detect PFM or SET mRNA orpolypeptide expression in a sample, or in screening methods to identifycompounds and cellular molecules that bind PFM or SET polypeptides andmodulate cell proliferation.

[0101] In one embodiment, the invention provides an isolatedpolypeptide, containing a PFM/SET amino acid sequence selected from thegroup consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and 20.Also provided are PFM/SET polypeptides that have at least 80% identitythereto. Further provided are isolated PFM/SET polypeptides having atleast about 90%, 95% and 98% identity with a reference PFM/SETpolypeptide amino acid sequence.

[0102] Exemplary isolated polypeptides provided by the invention arePFM/SET polypeptides having the sequence of SEQ ID NOS:2, 4, 6, 8, 10,12, 14, 16, 18 or 20.

[0103] The term “isolated,” in reference to a PFM/SET polypeptide of theinvention, is intended to mean that the molecule is substantiallyremoved or separated from components with which it is naturallyassociated, or otherwise modified by the hand of man. Thus, the term“isolated PFM/SET polypeptide” excludes PFM and SET polypeptides as theyexist in nature.

[0104] Isolated PFM/SET polypeptides that have at least about 90%, 95%and 98% identity with a reference PFM/SET polypeptide amino acidsequence can further be immunologically equivalent to a referencePFM/SET polypeptide. An immunologically equivalent PFM/SET polypeptidecan be recognized by an antibody that also specifically binds to thereference PFM/SET sequence. Specific binding refers to high affinitybinding of an antibody to the subject polypeptide, and binding withsubstantially lower affinity to an unrelated polypeptide, such as bovineserum albumin. High affinity binding includes binding with adissociation constant (Kd) of less than about 10⁻⁶ M, preferably lessthan about 10⁻⁷ M, such as less than about 10⁻⁸ M. Methods ofdetermining binding affinity are well known in the art and aredescribed, for example, in Harlow and Lane, Antibodies: A LaboratoryManual, Cold Spring Harbor Laboratory, New York (1989).

[0105] Those skilled in the art understand that two polypeptides with ahigh percentage of identity over the entire sequence, or over asubstantial portion of the sequence, are more likely to exhibit similarbiological activities than two molecules with the same percentageidentity over a shorter portion of the sequence. Furthermore, twopolypeptides that fold into common epitope structures are also morelikely to exhibit similar biological activities than two molecules thatdo not share a common three-dimensional structure. Accordingly, an aminoacid sequence that is “immunologically equivalent” to a PFM/SETpolypeptide can further be “functionally equivalent” to a PFM/SETpolypeptide. An exemplary “functionally equivalent” PFM/SET polypeptideis a PFM/SET “functional fragment.”

[0106] The invention further provides a modification of a PFM/SETpolypeptide. As used herein, a “modification” of a PFM/SET polypeptideof a reference amino acid sequence can include one or more additions,deletions or substitutions with respect to the reference sequence. Inparticular, a modification can include a conservative substitution, suchas substitution of an apolar amino acid with another apolar amino acid(such as replacement of leucine with isoleucine), or substitution of acharged amino acid with a similarly charged amino acid (such asreplacement of a glutamic acid with an aspartic acid). A modificationcan also include a nonconservative change, wherein a substituted aminoacid has different but sufficiently similar structural or chemicalproperties that permits such a substitution without adversely affectingthe desired immunological or biological activity.

[0107] A “modification” of a reference amino acid sequence that is“immunologically equivalent” or “biologically equivalent” to thereference amino acid sequence can also be a chemical or enzymaticmodification, including but not limited to replacement of hydrogen by analkyl, acyl, or amino group; esterification of a carboxyl group with asuitable alkyl or aryl moiety; alkylation of a hydroxyl group to form anether derivative; phosphorylation or dephosphorylation of a serine,threonine or tyrosine residue; or−or O-linked glycosylation.

[0108] Exemplary “modifications” of the recited PFM or SET sequencesinclude sequences that correspond to homologs of other species, such asprimates, mouse, rat, rabbit, bovine, porcine, ovine, canine or felinespecies. Furthermore, exemplary “modifications” of the recited PFM orSET sequences can correspond to splice variant forms, or internaltranslation products, of a recited PFM or SET sequence. Thus, forexample, a modification of a PFM polypeptide of the invention can lackone or more of the A, B or C boxes of the PR domain.

[0109] Those skilled in the art can determine appropriate amino acidmodifications for a given application. For example, a modification canserve to increase the stability, bioavailability, bioactiviy orimmunogenicity of the polypeptide, or to facilitate its purification.Thus, introduction of a D-amino acid or an amino acid analog for itscorresponding L-amino acid, or deletion of a lysine residue, canstabilize a polypeptide and reduce degradation. Addition of tagsequences, such as epitope tags, histidine tags,glutathione-S-transferase (GST) and the like, or addition of sortingsequences, can facilitate purification of a recombinant polypeptide.Addition of carrier sequences, such as keyhole limpet hemocyanin, canenhance recognition of the polypeptide by the immune system. Dependingon the modification and the source of the polypeptide, the modificationcan be introduced into the polypeptide, or into the encoding nucleicacid sequence.

[0110] Computer programs known in the art can provide guidance indetermining which amino acid residues can be modified as indicated abovewithout abolishing the immunological activity or a desired biologicalactivity of a PFM/SET polypeptide (see, for example, Eroshkin et al.,Comput. Appl. Biosci. 9:491-497 (1993)). Additionally, guidance inmodifying amino acid sequences while retaining functional activity isprovided by aligning homologous PFM/SET polypeptides from variousspecies. Those skilled in the art understand that evolutionarilyconserved amino acid residues and domains are more likely to beimportant for maintaining biological activity than less well-conservedresidues and domains.

[0111] In yet another embodiment, the invention provides an isolatedPFM/SET peptide, having at least 8 contiguous amino acids of SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18 or 20. As used herein, the term“PFM/SET peptide” refers to a peptide having at least 8 contiguous aminoacids of PFM/SET amino acid sequence. The amino acid length offunctional fragments, peptides or polypeptide analogs of the presentinvention can range from about 8 amino acids up to the full-lengthprotein sequence of an invention PR/SET polypeptide.

[0112] In certain embodiments, the amino acid lengths include, forexample, at least about 10 amino acids, at least about 15, at leastabout 20, at least about 25, at least about 30, at least about 35, atleast about 40, at least about 45, at least about 50, at least about 55,at least about 60, at least about 65, at least about 70, at least about75, at least about 80, at least about 85, at least about 90, at leastabout 95, at least about 100, at least about 125, at least about 150, atleast about 175, at least about 200, at least about 250 or more aminoacids in length up to the full-length PFM/SET polypeptide sequence. Apeptide of at least about 8 amino acids can be used, for example, as animmunogen to raise antibodies specific for an invention PFM/SETpolypeptide.

[0113] A peptide of such size contains at least one epitope specific toPFM/SET, and can thus be used as an immunogen to producePFM/SET-specific antibodies, or as an antigen to purify PFM/SETantibodies. PFM/SET peptides that are likely to be antigenic orimmunogenic can be predicted using methods and algorithms known in theart and described, for example, by Irnaten et al., Protein Eng.11:949-955 (1998), and Savoie et al., Pac. Symp. Biocomput. 1999:182-189(1999). Immunogenicity of the PFM or SET peptides of the invention canbe determined by methods known in the art, such as assay of adelayed-type hypersensitivity response in an animal sensitized to aPFM/SET polypeptide, or by elicitation of PFM/SET specific antibodies.Likewise, antigenicity of the PFM/SET peptides of the invention can bedetermined by methods known in the art, such as by ELISA analysis, asdescribed, for example, in Harlow and Lane, supra (1988).

[0114] As disclosed herein, the PFM/SET polypeptides of the inventionshare several biological activities. The biological activities ofPFM/SET polypeptides include, for example, growth modulating activity,regulation of chromatin-mediated gene expression, specific binding tocellular proteins, specific binding to DNA, methyltransferase activityand other biological activities described herein. The biologicalactivities of a PFM/SET polypeptide can be mediated by a domain within afull length PFM/SET polypeptide.

[0115] Therefore, the invention provides a PFM/SET polypeptide that is afunctional fragment of a PFM/SET polypeptide, said fragment comprising aPR, SET, PRAZ, or PKZL domain of a PFM/SET amino acid sequence selectedfrom the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18and 20.

[0116] As used herein, the term “functional fragment” is intended tomean a portion of a PFM/SET polypeptide that has one or more of thebiological activities characteristic of the reference polypeptide. Asused herein, the term “fragment” refers to any truncated form, eithercarboxy-terminal, amino-terminal, or both, of the reference PFM/SETpolypeptide. A functional fragment has an amino acid length required tomaintain a portion of the biological activities characteristic of thereference PFM/SET polypeptide, from a few amino acids to a one aminoacid deletion of the full length PFM/SET amino acid sequence.

[0117] In certain embodiments, the amino acid lengths of a functionalfragment include, for example, at least about 10 amino acids, at leastabout 15, at least about 20, at least about 25, at least about 30, atleast about 35, at least about 40, at least about 45, at least about 50,at least about 55, at least about 60, at least about 65, at least about70, at least about 75, at least about 80, at least about 85, at leastabout 90, at least about 95, at least about 100, at least about 125, atleast about 150, at least about 175, at least about 200, at least about250 or more amino acids in length up to a one amino acid deletion of afull-length PFM/SET polypeptide sequence. The functional fragments canbe contiguous amino acid sequences of an invention polypeptide,including contiguous amino acid sequences of SEQ ID NOS:2, 4, 6, 8, 10,12, 14, 16, 18 and 20.

[0118] A functional fragment of a PFM/SET polypeptide can containexogenous amino acid sequence that is not contained in a naturallyoccurring PFM/SET polypeptide. Exemplary exogenous amino acid sequencesare tags that facilitate identification or purification of a PFM/SETpolypeptide, such as histidine tags, glutathione-S transferase tags,FLAG tags and myc tags.

[0119] For example, a functional fragment of an invention polypeptidecan contain or consist of one or more of the following: a PR domain, aSET domain, a zinc finger domain, a PKZL domain, a PRAZ domain or anacidic region. In a specific example, a fragment of a PFM/SETpolypeptide can contain a zinc finger domain and PRAZ domain, but lack afunctional PR domain. Such a fragment will maintain a portion of thenaturally occurring biological activities of the PFM/SET polypeptide,but not all such activities. For example, such a PR domain-minuspolypeptide would lack methyltransferase activity. The resultantfragment will therefore have an activity different than the referencePFM/SET polypeptide. In another example, the PFM/SET polypeptide mighthave only the PR domain, allowing it to have methyltransferase activity.The activity of the fragment can be, for example, “dominant-negative.” Adominant-negative activity will allow the fragment to reduce orinactivate the activity of one or more isoforms of a naturally occurringPFM/SET polypeptide. Another functional fragment can include a PRAZdomain, or any of the domains disclosed herein.

[0120] Another biological activity of a PFM/SET polypeptide is theability to act as an immunogen for the production of antibodies, orother antigen binding molecules, that bind specifically to an inventionPFM/SET polypeptide.

[0121] The PFM/SET peptides of the invention can also be used inscreening methods to identify PFM/SET-binding cellular molecules andmodulatory compounds, as described further below.

[0122] The isolated PFM/SET polypeptides and peptides of the inventioncan be prepared by methods known in the art, including biochemical,recombinant and synthetic methods. For example, PFM and SET polypeptidescan be purified by routine biochemical methods from a cell or tissuesource that expresses abundant amounts of the corresponding transcriptor polypeptide. The diagnostic methods disclosed herein can be adaptedfor determining which cells and tissues, and which subcellular fractionstherefrom, are appropriate starting materials. Biochemical purificationcan include, for example, steps such as solubilization of theappropriate tissue or cells, isolation of desired subcellular fractions,size or affinity chromatography, electrophoresis, and immunoaffinityprocedures. The methods and conditions for biochemical purification of apolypeptide of the invention can be chosen by those skilled in the art,and purification monitored, for example, by an ELISA assay or afunctional assay, such as a DNA-binding or protein-binding assay.

[0123] A PFM/SET polypeptide, functional fragment or peptide having anydesired boundaries, and a polypeptide having a modification to thenative PFM or SET amino acid sequences, can also be produced byrecombinant methods. Recombinant methods involve expressing a nucleicacid molecule encoding the desired polypeptide or fragment in a hostcell or cell extract, and isolating the recombinant polypeptide orfragment, such as by routine biochemical purification methods describedabove. To facilitate identification and purification of the recombinantpolypeptide, it is often desirable to insert or add, in-frame with thecoding sequence, nucleic acid sequences that encode epitope tags,polyhistidine tags, glutathione-S-transferase (GST) domains, and similaraffinity binding sequences, or sequences that direct expression of thepolypeptide in the periplasm or direct secretion. Methods for producingand expressing recombinant polypeptides in vitro and in prokaryotic andeukaryotic host cells are well known in the art.

[0124] Thus, the invention provides a method of isolating a PFM/SETpolypeptide, by growing a host cell containing an expression vectorencoding a PFM or SET polypeptide, under conditions appropriate forexpression of the encoded PFM/SET polypeptide, and isolating the PFM/SETpolypeptide.

[0125] The PFM/SET polypeptide fragments and peptides of the inventioncan also be produced, for example, by enzymatic or chemical cleavage ofthe full-length polypeptide. Methods for enzymatic and chemical cleavageand for purification of the resultant peptide fragments are well knownin the art (see, for example, Deutscher, Methods in Enzymology, Vol.182, “Guide to Protein Purification,” San Diego: Academic Press, Inc.(1990), which is incorporated herein by reference).

[0126] Furthermore, PFM/SET polypeptides and peptides can be produced bychemical synthesis. If desired, such as to optimize their functionalactivity, stability or bioavailability, such molecules can be modifiedto include D-stereoisomers, non-naturally occurring amino acids, andamino acid analogs and mimetics. Examples of modified amino acids andtheir uses are presented in Sawyer, Peptide Based Drug Design, ACS,Washington (1995) and Gross and Meienhofer, The Peptides: Analysis,Synthesis, Biology, Academic Press, Inc., New York (1983), both of whichare incorporated herein by reference.

[0127] PFM/SET antibodies

[0128] The invention also provides an antibody or antigen bindingfragment thereof which specifically binds a PFM/SET polypeptide. Suchantibodies can be used, for example, to affinity purify a PFM/SETpolypeptide from a cell or tissue source, or in therapeutic anddiagnostic applications described below.

[0129] An “antigen binding fragment” of an antibody of the inventionincludes, for example, individual heavy or light chains and fragmentsthereof, such as VL, VH and Fd; monovalent fragments, such as Fv, Fab,and Fab′; bivalent fragments such as F(ab′)₂; single chain Fv (scFv);and Fc fragments. Antigen binding fragments include, for example,fragments produced by protease digestion or reduction of an antibody, aswell as fragments produced by recombinant DNA methods known to thoseskilled in the art.

[0130] The antibodies of the invention can be produced by any methodknown in the art. For example, a PFM or SET polypeptide or immunogenicpeptide of the invention, or a nucleic acid expressing such apolypeptide, can be administered to an animal, using standard methods,and polyclonal antibodies isolated therefrom. Such polypeptides ofpeptides, if desired, can be conjugated to a carrier, such as KLH, serumalbumin, tetanus toxoid and the like, using standard linking techniques,to increase their immunogenicity. Additionally, such peptides can beformulated together with an adjuvant known in the art, such as Freund'scomplete or incomplete adjuvant. The antibodies so generated can be usedin the form of serum isolated from an immunized animal, or the antibodycan be affinity purified from the serum using PFM/SET peptides orpolypeptides.

[0131] Additionally, the PFM/SET antibodies of the invention can bemonoclonal antibodies produced by a hybridoma cell line, by chemicalsynthesis, or by recombinant methods. Modified antibodies, such aschimeric antibodies, humanized antibodies and CDR-grafted orbifunctional antibodies, can also be produced by methods well known tothose skilled in the art.

[0132] Methods of preparing and using antibodies and antigen-bindingfragments, including detectably labeled antibodies, are described, forexample, in Harlow and Lane, Antibodies: A Laboratory Manual, ColdSpring Harbor Laboratory, New York (1989); in Day, E. D., AdvancedImmunochemistry, Second Ed., Wiley-Liss, Inc., New York, N.Y. (1990);and in Borrebaeck (Ed.), Antibody Engineerinq, Second Ed., OxfordUniversity Press, New York (1995), which are incorporated herein byreference.

[0133] PFM/SET modulatory compounds

[0134] The invention also provides methods of identifying cellular andnon-cellular molecules that modulate PFM/SET expression and activity. Asused herein, the term “PFM/SET modulatory compound” refers to a moleculethat alters PFM/SET expression or activity. A PFM/SET modulatorycompound can increase or decrease PFM/SET expression or activity. Suchcompounds can be used in ex vivo and in vivo therapeutic applications,as described further below, to promote or inhibit cell proliferation.

[0135] As disclosed herein, the PR and SET domains of the PFM/SETpolypeptides of the invention have methyltransferase enzymatic activityand function as specific protein binding domains. Through themethyltransferase activity and specific binding to particular cellularproteins, the intact PR/SET domain contributes to the function ofPFM/SET polypeptide as a suppressor of cell growth. Therefore, a PFM/SETmodulatory compound can alter the activity of a PFM/SET polypeptide bymodulating the enzymatic activity or the molecular interactions of aPFM/SET with another molecule. A PFM/SET modulatory compound can alsoalter the amount of a PFM/SET polypeptide expressed in a cell, forexample, by increasing or decreasing the cellular expression level orstability of a PFM/SET polypeptide.

[0136] A PFM/SET modulatory compound can be identified by contacting aPFM/SET-expressing cell with a candidate compound under conditions thatallow PFM/SET expression or activity. Expression of a PFM/SET refers tothe generation of a PFM/SET mRNA or polypeptide. Therefore, an amount ofPFM/SET expression can be represented by an amount of messenger RNA(mRNA) or an amount of polypeptide corresponding to a PFM/SET mRNA. Anamount of PFM/SET mRNA expressed in a particular cell is generallydetermined by the transcriptional activity of the gene encoding the mRNAas well as the stability of the mRNA. The amount of polypeptideexpressed in a particular cell is generally determined by the stabilityof the polypeptide and susceptibility to proteolysis of the polypeptide.An increase in PFM/SET can result, for example, from an increase in theamount of PFM/SET mRNA resulting from increased transcription of aPFM/SET gene, increased stability of PFM/SET mRNA and reduceddegradation of PFM/SET mRNA. An alteration in the amount of PFM/SETpolypeptide can result, for example, from increased or decreasedstability and increased or decreased proteolysis of a PFM/SETpolypeptide. An increase in PFM/SET activity can result, for example,from an increase in the amount of PFM/SET polypeptide or alteration inPFM/SET structure or conformation that leads to increased activity,including a modification of a PFM/SET polypeptide.

[0137] A PFM/SET modulatory compound can act to modulate PFM/SETactivity by increasing or decreasing the amount of PFM/SET polypeptidein a cell, for example, by stimulating increased PFM/SET mRNAexpression. PFM/SET mRNA expression can be modulated, for example, byinducing or derepression the transcription of a PFM/SET gene and byregulating the expression of a cellular protein that acts as atranscription factor to regulate gene expression. A compound can act tomodulate the amount of PFM/SET activity by increasing or decreasing thestability of a PFM/SET mRNA or polypeptide, for example, by increasingor decreasing a cellular degradation activity, such as a proteaseactivity. Molecules that mediate the regulation of PFM/SET expression,such as receptors and corresponding signal transduction molecules, canalso be targets of compounds that increase the expression of PFM/SET ina cell. For example, a signal transduction pathway that stimulates theexpression of PFM/SET can be modulated to increase or decrease the levelof PFM/SET expression, for example, by increasing or decreasing the rateof PFM/SET synthesis or the length of time that PFM/SET gene expressionremains active.

[0138] A compound can directly increase or decrease PFM/SET activity,for example, by binding to the enzyme and modulating catalytic activity,such as by inducing a conformational change in the PFM/SET polypeptide.A compound that directly increases or decreases the activity of aPFM/SET polypeptide can be identified by contacting a candidate compoundwith a PFM/SET polypeptide or functional fragment thereof, contained ina cell, cell fraction, or lysate thereof, and can be an isolated PFM/SETpolypeptide. A compound that modulates the interaction of a PFM/SETpolypeptide with a binding partner can also be identified by contactinga candidate compound with a PFM/SET polypeptide or functional fragmentthereof in the presence of a binding partner. Methods for identifyingPFM/SET binding partners are well known to those skilled in the art andare described below.

[0139] A compound that binds to and modulates the activity of a PFM/SETpolypeptide can be identified using a variety of binding assay formats.A binding assay can use a detectably labeled candidate compound and anunlabeled PFM/SET (and optionally an unlabeled binding partner).Alternatively, a binding assay can use an unlabeled candidate compoundor binding partner and a labeled PFM/SET. Other appropriate combinationsof labeled and unlabeled molecules can be determined by the skilledperson depending on the assay format.

[0140] A variety of low- and high-throughput assays known in the art aresuitable for detecting specific binding interactions between a PFM/SETnucleic acid molecule or polypeptide and a candidate PFM/SET modulatorycompound. These assays include both solution-based methods and solidphase methods (e.g. molecules bound to plates, chips, affinity columnsand the like). Binding assays are amenable to either manual orhigh-throughput automated screening of compounds.

[0141] Both direct and competitive binding assays can be performed,including, for example, scintillation proximity assay (SPA) (Alouani,Methods Mol. Biol. 138:135-41 (2000)), UV or chemical cross-linking(Fancy, Curr. Opin. Chem. Biol. 4:28-33 (2000)), competition bindingassays (Yamamura et al., Methods in Neurotransmitter Receptor Analysis,Raven Press, New York, 1990), biomolecular interaction analysis (BIA)(Weinberger et al., Pharmacogenomics 1:395-416 (2000)), massspectrometry (MS) (McLafferty et al., Science 284:1289-1290 (1999) andDegterev, et al., Nature Cell Biology 3:173-182 (2001)), nuclearmagnetic resonance (NMR) (Shuker et al., Science 274:1531-1534 (1996),Hajduk et al., J. Med. Chem. 42:2315-2317 (1999), and Chen and Shapiro,Anal. Chem. 71:669A-675A (1999)), and fluorescence polarization assays(FPA) (Degterev et al., supra, 2001) which are incorporated herein byreference. Other assays for detecting specific binding interactionsinclude, for example ELISA assays, FACs analysis, and affinityseparation methods, which as described, for example, in Harlow and Lane,Eds. Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory(1988).

[0142] Assays to identify compounds that modulate PFM/SET geneexpression can involve first transducing cells with a PFM or SETpromoter-reporter nucleic acid construct such that a change inexpression of a protein such as β-lactamase, luciferase, greenfluorescent protein or β-galactosidase will be detected in response tocontacting the cell with a PFM/SET modulatory compound that upregulatesor downregulates expression of PFM or SET. Assays and reporter systemsuseful for monitoring gene expression are well known in the art. Otherassays to identify compounds that modulate PFM/SET gene expressioninclude assays that measure levels of PFM or SET transcripts, such asNorthern blots, RNase protection assays, and RT-PCR.

[0143] Assays to identify compounds that modulate PFM/SET polypeptideexpression can involve detecting a change in PFM or SET polypeptideabundance in response to contacting the cell with a PFM or SETmodulatory compound. Assays for detecting changes in polypeptideexpression include, for example, immunoassays with specific PFM or SETantibodies, such as immunofluorescence, immunohistochemistry andimmunoprecipitation assays.

[0144] Appropriate assays to determine whether a PFM/SET modulatorycompound affects PFM or SET activity so as to inhibit or promote cellproliferation, can be determined by those skilled in the art. Theskilled artisan appreciates that molecular pathways involved in cellproliferation are generally well conserved among eukaryotic organisms.Therefore, a proliferation assay can be performed in any eukaryotic celltype in which altered proliferation can be detected including, forexample, primary mammalian cells, normal and transformed mammalian celllines, yeast, insect cells and amphibian cells.

[0145] A molecule that modulates cell proliferation can, for example,cause cell cycle arrest at a particular stage of mitosis or meiosis,induce or prevent apoptosis, or promote progression through the cellcycle when normal cells would arrest. Such qualitative changes in thecell cycle can be determined by methods known in the art, and whichdepend on the cell type used in the assay. A molecule that modulatescell proliferation can also, for example, cause faster or slowerprogression through the cell cycle, resulting in an increased ordecreased number of cells in the population after a given period oftime. Those skilled in the art can choose an appropriate assay todetermine whether, and by what mechanism, a molecule of the inventionaffects cell proliferation.

[0146] A molecule that modulates cell proliferation can also restoremore normal proliferative characteristics to a neoplastic cell. Such amolecule can advantageously be used in therapeutic applications toprevent or treat cancer. To determine whether a molecule of theinvention restores more normal proliferative characteristics on aneoplastic cell, an assay can be performed in a mammalian cell thatexhibits neoplastic proliferative characteristics, such as soft agarcolony formation, overgrowth of a cell monolayer, proliferation in lowserum, abnormally rapid proliferation, or tumor formation in an animal.Such cells are known in the art and include both tumor cell lines andprimary tumor cells. A molecule of the invention can be introduced orexpressed in such a cell, and a determination can be made whether themolecule restores more normal proliferative characteristics to the cell,such as slower growth in culture, fewer foci, fewer soft agar colonies,or a reduction in tumor size, as compared to the parental cell.

[0147] The methods of identifying a PFM/SET modulatory compound caninvolve measuring changes in gene expression by determining the amountof mRNA or polypeptide present in a sample. Methods for measuring bothmRNA and polypeptide quantity are well known in the art. Methods formeasuring mRNA typically involve detecting nucleic acid molecules byspecific hybridization with a complementary probe in solution or solidphase formats. Such methods include northern blots, polymerase chainreaction after reverse transcription of RNA (RT-PCR), and nucleaseprotection. Measurement of a response of a pathway component can beperformed using large scale gene expression methods. For methods of theinvention that involve identifying a candidate atherosclerosis drugtarget molecule, described below, large scale gene expression methodscan be advantageously used to measure a large population of expressedgenes in an organ, tissue or cell. Examples of methods well known in theart applicable to measuring a change in expression of a population ofgenes include cDNA sequencing, clone hybridization, differentialdisplay, subtractive hybridization, cDNA fragment fingerprinting, serialanalysis of gene expression (SAGE), and DNA microarrays.

[0148] A variety of methods well known in the art can be used todetermine protein levels either directly or indirectly. Such methodsinclude immunochemical methods, such as western blotting, ELISA,immunoprecipitation, and RIA, gel electrophoresis methods including oneand two-dimensional gels, methods based on protein or peptidechromatographic separation, methods that use protein-fusion reporterconstructs and calorimetric readouts, methods based on characterizationof actively translated polysomal mRNA, and mass spectrometric detection.

[0149] The methods of the invention for identifying a PFM/SET modulatorycompound can involve determining an activity of PFM/SET. Exemplaryactivities include, for example, transcriptional activity andmethyltransferase activity (see, for example, Huang et al., J. Biol.Chem. 273:15933-15939 (1998). Suitable assays for identifying compoundsthat modulate PFM/SET transcriptional activation, repression andcoactivation function can be determined by the skilled person. Suchassays are generally based on co-expression of PFM/SET and anappropriate promoter-linked reporter gene in a cell, under conditionswhere a certain amount of transcription occurs, contacting the cell withthe candidate compound, and determining whether there is a change (i.e.either an increase or decrease) in transcriptional activity.Transcription based assays are well known in the art, and readilyamenable to high-throughput screening assays.

[0150] Methyltransferase activity assays are also well known in the art,and generally involve measuring the amount of transfer of a labeledmethyl group from a donor molecule (e.g. radiolabeled S-adenosyl-methionine) to a protein, and determining any change in this activity inresponse to a candidate compound.

[0151] Methyltransferase activity assays are described, for example, inChen et al., Science 284:2174-2177 (1999).

[0152] PF, SET, PRAZ and PKZL domains of a PFM/SET polypeptide can bindto cellular proteins and thereby regulate a PFM/SET biological activity.Therefore, an isolated PFM/SET polypeptide, including a functionalfragment of a PFM/SET polypeptide that contains a PR, SET, PRAZ or PKZLdomain, can be used in assays to identify compounds that modulate theinteraction of a PFM/SET polypeptide with another cellular molecule.

[0153] Various binding assays to identify cellular proteins thatinteract with protein binding domains are known in the art and include,for example, yeast two-hybrid screening assays (see, for example, Lubanet al., Curr. Opin. Biotechnol. 6:59-64 (1995)) and affinity columnchromatography methods using cellular extracts. By synthesizing orexpressing polypeptide fragments containing various PFM or SET sequencesor deletions, the PFM or SET binding interface can be readilyidentified.

[0154] As further disclosed herein, the zinc finger (ZF) domain of thePFM polypeptides of the invention functions as a specific DNA bindingdomain. By specifically binding particular DNA sequences, the ZF domaincontributes to the function of PFM/SET polypeptides as a suppressor ofcell growth. Thus, an isolated PFM/SET polypeptide of the inventioncontaining a ZF domain, or one or more ZF motifs therefrom, can be used,for example, in binding assays to identify cellular DNA sequences thatnormally bind PFM. Such cellular DNA sequences are likely to beregulatory sequences for genes which themselves have positive ornegative growth modulating activity, and which are appropriate targetsfor therapeutic intervention to prevent or treat proliferativedisorders. Furthermore, oligonucleotides or analogs corresponding thePFM binding DNA sequences, can be administered as therapeutic compoundsto specifically interfere with PFM function. Additionally, the ZFdomain, or one or more ZF motifs therefrom, can be administered astherapeutic compounds to specifically interfere with PFM function.

[0155] Various assays to identify DNA sequences that bind DNA bindingdomains are known in the art and include, for example, CyclicAmplification and Selection of Targets (CASTing), as described by Wrightet al., Mol. Cell. Biol. 11:4104-4110 (1991), and the MultiplexSelection Technique (MuST), as described by Nallur et al., Proc. Natl.Acad. Sci. USA 93:1184-1189 (1996).

[0156] As understood by those of skill in the art, assay methods foridentifying compounds that increase PFM/SET activity generally requirecomparison to a control. One type of a “control” is a cell or isolatedPFM/SET polypeptide preparation that is treated substantially the sameas the test cell exposed to a candidate compound, except that a controlis not exposed to a compound. A control cell or isolated PFM/SETpolypeptide can be treated with a carrier solution or solvent in which acandidate compound is dissolved or contained, such as an aqueous ororganic solution, if desired.

[0157] Given the teachings and guidance provided herein, the choice ofmeasuring MRNA or polypeptide amount or polypeptide activity will bethat of the user. Considerations such as the sample type, availabilityand amount will also influence selection of a particular assay format.For example, if a small amount of sample is available, formats which aremore sensitive are suitable. Alternatively, if the user is analyzingnumerous different samples simultaneously, a multisample format issuitable. Those skilled in the art will know, or can determine, whichformat is useful for a particular application and which methods ormodifications of methods known in the art are compatible with aparticular assay format.

[0158] A PFM/SET modulatory compound can be a naturally occurringmacromolecule, such as a peptide, nucleic acid, carbohydrate, lipid, orany combination thereof. A PFM/SET modulatory compound also can be apartially or completely synthetic derivative, analog or mimetic of sucha macromolecule, or a small organic or inorganic molecule preparedpartly or completely by combinatorial chemistry methods.

[0159] Methods for producing pluralities of compounds to use inscreening for PFM/SET modulatory compounds, including chemical orbiological molecules such as simple or complex organic molecules,metal-containing compounds, carbohydrates, peptides, proteins,peptidomimetics, glycoproteins, lipoproteins, nucleic acids, antibodies,and the like, are well known in the art and are described, for example,in Huse, U.S. Pat. No. 5,264,563; Francis et al., Curr. Opin. Chem.Biol. 2:422-428 (1998); Tietze et al., Curr. Biol., 2:363-371 (1998);Sofia, Mol. Divers. 3:75-94 (1998); Eichler et al., Med. Res. Rev.15:481-496 (1995); and the like. Libraries containing large numbers ofnatural and synthetic compounds also can be obtained from commercialsources.

[0160] Therapeutic applications

[0161] As disclosed herein, PFM/SET nucleic acid molecules encoding PFMor SET polypeptides with intact PR/SET domains inhibit cell growth. Incontrast, PFM/SET nucleic acid molecules encoding PFM or SETpolypeptides with partial PR/SET domains, or lacking PR/SET domains,promote cell growth. Thus, by selectively manipulating the expression oractivity of either the PR/SET+ or PR/SET− forms of the PFM/SET moleculesof the invention, or both, it is readily apparent that cell growth canbe modulated in either a positive or negative manner, as desired.

[0162] Accordingly, the invention provides PFM/SET molecules andtherapeutic methods that can be used to inhibit the growth of cells inculture, or in a subject. Advantageously, the molecules and therapeuticmethods can be used to treat proliferative disorders in a subject. Asused herein, the term “proliferative disorder” refers to a condition inwhich unwanted cell proliferation of one or more subset of cells in amammal, such as a human, occurs, resulting in harm (e.g., discomfort ordecreased life expectancy) to the mammal. Cell proliferative disordersinclude diseases such as cancer, in which the cells are neoplasticallytransformed, but also include diseases resulting from overgrowth ofnormal cells. For example, cell proliferative disorders include diseasesassociated with the overgrowth of connective tissues, such as variousfibrotic diseases, including scleroderma, arthritis, alcoholic livercirrhosis, keloid, and hypertropic scarring; vascular proliferativedisorders, such as atherosclerosis; and benign tumors.

[0163] The invention also provides PFM/SET molecules and therapeuticmethods that can be used to enhance proliferation of normal cells. Forsome therapeutic applications, it may be useful to increase theproliferation of normal cells, without rendering the cells cancerous. Inparticular, in diseases of cell degeneration, such as Duchenne'smuscular dystrophy, insulin-dependent diabetes mellitus, Parkinson'sdisease, Huntington's disease, Alzheimer's disease, paralysis,cerebellar atrophy, and the like, it may be useful to remove some of theremaining normal cells from the affected tissue of the individual, andculture the cells in large numbers ex vivo for reimplantation into thepatient. Additionally, in applications such as wound healing and skingrafts, it is often desirable to increase the proliferation of normalcells.

[0164] In one embodiment, the invention provides a method for modulatingcell growth, by introducing a vector containing an isolated PFM6, PFM7,PFM8, PFM9, PFM10, PFM11, PFM12, PFM13, PFM14 or SET07 nucleic acidmolecule of the invention, operatively linked to a promoter of RNAexpression, into a host cell, and expressing the encoded PFM/SETpolypeptide in an amount effective to modulate growth of the cell. Forapplications in which inhibition of cell growth is desirable, expressionvectors containing isolated full-length PFM/SET nucleic acid molecules,or modifications of full-length PFM/SET nucleic acid molecules thatretain the growth inhibitory activity of PFM/SET, can be introduced intocells under conditions in which the PFM/SET polypeptide is expressed inan effective amount to inhibit cell proliferation. For applications inwhich promotion of cell growth is desirable, expression vectors whichcontain portions of the PFM/SET nucleic acid molecules that compete withPFM/SET for substrates or effectors, such as the PR domain or zincfinger domain, or both, can be introduced into cells under conditions inwhich the PFM/SET polypeptide is expressed in an effective amount topromote cell proliferation.

[0165] Various gene therapy strategies are well known to those skilledin the art, and are reviewed, for example in Roth et al., Oncoloqy 13(10Suppl 5):148-54, (1999). Useful mammalian expression vectors for suchtherapeutic applications, and methods of introducing such vectors intomammalian cells either ex vivo or in vivo, for expression of the encodedpolypeptide, are well known in the art. Viruses are specializedinfectious agents that can elude host defense mechanisms and can infectand propagate in specific cell types. Viral based systems provide theadvantage of being able to introduce relatively high levels of theheterologous nucleic acid into a variety of cells. Suitable viralvectors for introducing an invention PFM/SET nucleic acid into mammaliancells (e.g., vascular tissue segments) are well known in the art. Theseviral vectors include, for example, Herpes simplex virus vectors(Latchman, Histology and Histopathology, 15:1253-1259 (2000)), Vacciniavirus vectors, Cytomegalovirus vectors, Moloney murine leukemia virusvectors, adenovirus vectors, adeno-associated virus vectors, retrovirusvectors, lentiviral vectors and the like.

[0166] In particular, the specificity of viral vectors for particularcell types can be utilized to target predetermined cell types. Thus, theselection of a viral vector will depend, in part, on the cell type to betargeted. For example, if a proliferative disease is to be treated byincreasing the level of a PFM/SET polypeptide in a particular tissueaffected by the disease, then a viral vector that targets the particulartissue can be used. For example, if a disease or pathological conditionof the hematopoietic system is to be treated, then a viral vector thatis specific for a particular blood cell or its precursor cell can beused. A vector based on a human immunodeficiency virus is an example ofsuch a viral vector. In addition, a viral vector or other vector can beconstructed to express a PFM/SET nucleic acid in a tissue specificmanner by incorporating a tissue-specific promoter or enhancer into thevector.

[0167] Non-viral synthetic vectors and hybrid vectors are also usefulfor introducing a PFM/SET nucleic acid molecule of the invention into acell. Cell-based delivery methods involving ex vivo genetic manipulationof cells are also useful for delivering a PFM/SET nucleic acid moleculeinto a cell of an individual.

[0168] For gene therapy, a vector containing a PFM/SET nucleic acid oran antisense nucleotide sequence can be administered to a subject byvarious methods. For example, if viral vectors are used, administrationcan take advantage of the target specificity of the vectors. In suchcases, there in no need to administer the vector locally at the diseasedsite. However, local administration can be a particularly effectivemethod of administering a PFM/SET nucleic acid. In addition,administration can be via intravenous or subcutaneous injection into thesubject. Following injection, the viral vectors will circulate untilthey recognize host cells with the appropriate target specificity forinfection. Injection of viral vectors into the spinal fluid also can bean effective mode of administration, for example, in treating aneurodegenerative disease.

[0169] Receptor-mediated DNA delivery approaches also can be used todeliver a PFM/SET nucleic acid molecule into cells in a tissue-specificmanner using a tissue-specific ligand or an antibody that isnon-covalently complexed with the nucleic acid molecule via a bridgingmolecule. Direct injection of a naked or a nucleic acid moleculeencapsulated, for example, in cationic liposomes also can be used forstable gene transfer into non-dividing or dividing cells in vivo. Inaddition, a PFM/SET nucleic acid molecule can be transferred into avariety of tissues using the particle bombardment method. Such nucleicacid molecules can be linked to the appropriate nucleotide sequencesrequired for transcription and translation.

[0170] A particularly useful mode of administration of a PFM/SET nucleicacid is by direct inoculation locally at the site of the disease orpathological condition. Local administration can be advantageous becausethere is no dilution effect and, therefore, the likelihood that amajority of the targeted cells will be contacted with the nucleic acidmolecule is increased. Thus, local inoculation can alleviate thetargeting requirement necessary with other forms of administration and,if desired, a vector that infects all cell types in the inoculated areacan be used. If expression is desired in only a specific subset of cellswithin the inoculated area, then a promoter, an enhancer or otherexpression element specific for the desired subset of cells can belinked to the nucleic acid molecule. Vectors containing such nucleicacid molecules and regulatory elements can be viral vectors, viralgenomes, plasmids, phagemids and the like. Transfection vehicles such asliposomes also can be used to introduce a non-viral vector intorecipient cells. Such vehicles are well known in the art.

[0171] In another embodiment, the invention provides a method formodulating cell growth by introducing into a cell an effective amount ofan antisense oligonucleotide or a ribozyme that inhibits expression ofPFM/SET, thereby modulating growth of the cell. Methods for modulatinggene expression using antisense oligonucleotides and ribozymes are alsowell known in the art. Thus, an antisense molecule or ribozyme thatselectively inhibits expression of the PR/SET−, growth promoting form ofPFM/SET, can be used to inhibit cell proliferation. In contrast, anantisense molecule or ribozyme that selectively inhibits expression ofthe PR+, growth suppressing form of PFM/SET, can be used to promote cellproliferation.

[0172] Antisense oligonucleotides that inhibit PFM/SET gene expressiongenerally are at least about 17 nucleotides in length, and often includesequences found within the first 30 nucleotides of the transcript beingtargeted. The preparation and use of antisense oligonucleotides are wellknown in the art and described in detail, for example, in Cohen (ed),Oligonucleotides: Antisense Inhibitors of Gene Expression, CRC PressInc., Boca Raton (1989). Likewise, methods of preparing and usinghairpin and hammerhead ribozymes for the selective inhibition of geneexpression are known in the art and are described, for example, inPoeschla et al., Curr. Olin. Oncol. 6:601-606 (1994).

[0173] In a further embodiment, the invention provides a method formodulating cell growth by contacting the cell with an effective amountof a PFM/SET modulatory compound. Methods of identifying PFM/SETmodulatory compounds have been described above.

[0174] In yet another embodiment, the invention provides a method formodulating cell growth by administering antibodies that specificallybind a PFM or SET polypeptide. For example, antibodies that selectivelydetect a growth promoting structural variant of PFM or SET, such as thePR− form of PFM polypeptide, can be administered to selectively targetcells that express this variant. If desired, such antibodies can beadministered in conjunction with a cytotoxic or cytostatic moiety, suchas a radioisotope or toxin, in order to neutralize or kill cellsexpressing the desired structural variant.

[0175] The PFM/SET therapeutic molecules of the invention describedherein, including expression vectors, antisense oligonucleotides andribozymes, PFM/SET modulatory compounds, and antibodies, can optionallybe formulated together with a pharmaceutically acceptable carrier fordelivery to a cultured cell or to a subject. Suitable pharmaceuticallyacceptable carriers are well known in the art and include, for example,aqueous or organic solvents such as physiologically buffered saline,glycols, glycerol, oils or injectable organic esters. A pharmaceuticallyacceptable carrier can also contain a physiologically acceptablecompound that acts, for example, to stabilize or increase the solubilityof a pharmaceutical composition. Such a physiologically acceptablecompound can be, for example, a carbohydrate, such as glucose, sucroseor dextrans; an antioxidant, such as ascorbic acid or glutathione; achelating agent; a low molecular weight protein; or another stabilizeror excipient. Pharmaceutically acceptable carriers, including solvents,stabilizers, solubilizers and preservatives, are well known to thoseskilled in the art.

[0176] Those skilled in the art can formulate the therapeutic moleculesto ensure proper distribution in vivo. For example, the blood-brainbarrier (BBB) excludes many highly hydrophilic compounds. To ensure thatthe therapeutic molecules of the invention cross the BBB, if desired,they can be formulated, for example, in liposomes, or chemicallyderivatized. Methods of ensuring appropriate distribution in vivo canalso be provided by rechargeable or biodegradable devices, particularlywhere gradients of concentrations of drug in a tissue are desired.Various slow release polymeric devices are known in the art for thecontrolled delivery of drugs, and include both biodegradable and non-degradable polymers and hydrogels. Those skilled in the art understandthat the choice of the pharmaceutical formulation and the appropriatepreparation of the composition will depend on the intended use and modeof administration.

[0177] The therapeutic molecules of the invention, including expressionvectors, antisense oligonucleotides and ribozymes, PFM/SET modulatorycompounds and antibodies, can be administered to a subject by anyeffective route. Suitable routes for delivering the therapeuticmolecules of the invention include topically, intraocularly,intradermally, parenterally, orally, intranasally, intravenously,intramuscularly, intraspinally, intracerebrally and subcutaneously. In apreferred embodiment, the therapeutic PFM or SET molecules are directlyinjected into a solid tumor, tumor-containing organ or tumor containingbody cavity, in a effective amount to inhibit proliferation of the tumorcells. Alternatively, the therapeutic PFM or SET molecules of theinvention can be administered systemically into the blood or lymphaticcirculation to reach cells in the circulatory system or in any organ ortissue.

[0178] An effective dose of a therapeutic molecule of the invention canbe determined, for example, by extrapolation from the concentrationrequired for binding an isolated PFM/SET nucleic acid or polypeptide inbinding and functional assays described herein; from the dose requiredto modulate PFM or SET nucleic acid or polypeptide expression in theexpression assays described herein; or from the dose required tomodulate cell proliferation in the proliferation assays describedherein.

[0179] An effective dose of a molecule of the invention for thetreatment of proliferative disorders can also be determined fromappropriate animal models, such as xenografts of human tumors in rats ormice. Human cancer cells can be introduced into an animal by a number ofroutes, including subcutaneously, intraveneously and intraperitoneally.Following establishment of a tumor, the animals can be treated withdifferent doses of a molecule of the invention, and tumor mass or volumecan be determined. An effective dose for treating cancer is a dose thatresults in either partial or complete regression of the tumor, reductionin metastasis, reduced discomfort, or prolonged life span.

[0180] The appropriate dose for treatment of a human subject with atherapeutic molecule of the invention can be determined by those skilledin the art, and is dependent on the nature and bioactivity of theparticular compound, the desired route of administration, the gender,age and health of the individual, the number of doses and duration oftreatment, and the particular condition being treated.

[0181] Diagnostic applications

[0182] The PFM/SET nucleic acids and polypeptides disclosed herein existin different forms, depending on the splice variant expressed. PFMnucleic acids and polypeptides that express or contain an intact PRdomain (PR+) are associated with regulated, or normal, cellproliferation. A decrease in the total amount, or relative amount, ofthe PR+ form of a PFM, or an increase in the total amount, or relativeamount, of the PR− form of a PFM, is associated with unregulated, orpathological, cell proliferation. Therefore, determining the total orrelative abundance of the PR+and PR− forms of PFM, or identifyingalterations in the expression or structure of PFM nucleic acid moleculesor polypeptides, can be used to distinguish between normal andpathologically proliferative cells in a sample. Similarly, detection ofthe presence or absence of a SET domain in a PFM/SET nucleic acid orpolypeptide can be used to distinguish between normal and pathologicallyproliferative cells in a sample.

[0183] The invention thus provides methods of detecting PFM/SET nucleicacids and polypeptides in a sample. As used herein, the term “sample” isintended to mean any biological fluid, cell, tissue, organ or portionthereof, that includes or potentially includes PFM or SET nucleic acidsor polypeptides. The term includes samples present in an individual aswell as samples obtained or derived from the individual. For example, asample can be a histologic section of a specimen obtained by biopsy, orcells that are placed in or adapted to tissue culture. A sample furthercan be a subcellular fraction or extract, or a crude or substantiallypure nucleic acid or protein preparation. A sample can be prepared bymethods known in the art suitable for the particular format of thedetection method employed.

[0184] The detection methods of the invention can advantageously beused, for example, to identify pathologically proliferative cells, suchas neoplastic cells, in a sample. As used herein, the term “neoplasticcell” is intended to mean a cell that exhibits histological orproliferative features of a malignant or premalignant cell. For example,by histological methods, a neoplastic cell can be observed to invadeinto surrounding normal tissue, have an increased mitotic index, anincreased nuclear to cytoplasmic ratio, altered deposition ofextracellular matrix, or a less differentiated phenotype. A neoplasticcell can also exhibit unregulated proliferation, such as anchorageindependent cell growth, proliferation in reduced-serum medium, loss ofcontact inhibition, or rapid proliferation compared to normal cells. Thediagnostic methods described herein are applicable to the identificationof any type of neoplastic cell, such as neoplastic cells present insolid tumors (carcinomas and sarcomas) such as breast, colorectal,gynecological, lung, prostate, bladder, renal, liver, urethral,endocrinal, melanoma, basal cell, central nervous system, lymphoma,stomach, esophageal, squamous cell cancers, as well as all forms ofleukemias, and metastases therefrom.

[0185] The diagnostic methods described herein can also be adapted foruse as prognostic assays. Such an application takes advantage of theobservation that alterations in expression or structure of differenttumor suppressor molecules take place at characteristic stages in theprogression of a proliferative disease or of a tumor. Knowledge of thestage of the tumor allows the clinician to select the most appropriatetreatment for the tumor and to predict the likelihood of success of thattreatment.

[0186] The diagnostic methods described herein can also be used toidentify individuals at increased risk of developing a proliferativedisease, such as cancer, due to hereditary mutations in a PFM or SET.

[0187] The invention thus provides methods for detecting PFM/SET nucleicacid in a sample. In one embodiment, the method consists of contactingthe sample with an isolated PFM6, PFM7, PFM8, PFM9, PFM10, PFM11, PFM12,PFM13, PFM14 or SET07 nucleic acid molecule, under conditions that allowspecific hybridization to PFM/SET nucleic acid, and detecting specifichybridization.

[0188] In another embodiment, the method consists of contacting thesample with a PFM/SET primer pair, under conditions that allowamplification of PFM/SET nucleic acid, and detecting amplified PFM/SETnucleic acid.

[0189] The methods of detecting PFM/SET nucleic acid in a sample can beeither qualitative or quantitative, as desired. For example, thepresence, abundance, integrity or structure of a PFM/SET, or ofparticular splice variants thereof, can be determined, as desired,depending on the assay format and the probe or primer pair chosen.

[0190] Useful assays for detecting PFM/SET nucleic acid based onspecific hybridization with an isolated PFM/SET nucleic acid moleculeare well known in the art and include, for example, in situhybridization, which can be used to detect altered chromosomal locationof the nucleic acid molecule, altered gene copy number, and RNAabundance, depending on the assay format used. Other hybridizationassays include, for example, Northern blots and RNase protection assays,which can be used to determine the abundance and integrity of differentRNA splice variants, and Southern blots, which can be used to determinethe copy number and integrity of DNA. A PFM/SET hybridization probe canbe labeled with any suitable detectable moiety, such as a radioisotope,fluorochrome, chemiluminescent marker, biotin, or other detectablemoiety known in the art that is detectable by analytical methods.

[0191] Useful assays for detecting PFM/SET nucleic acid in a samplebased on amplifying PFM/SET nucleic acid with a PFM/SET primer pair arealso well known in the art, and include, for example, qualitative orquantitative polymerase chain reaction (PCR); reverse-transcription PCR(RT-PCR); SSCP analysis, which can readily identify a single pointmutation in DNA, such as in a PCR or RT-PCR product; and coupled PCR,transcription and translation assays, such as the Protein TruncationTest, in which a mutation in DNA is determined by an altered proteinproduct on an electrophoresis gel. Additionally, the amplified PFM/SETnucleic acid can be sequenced to detect mutations and mutationalhot-spots, and specific assays for large-scale screening of samples toidentify such mutations can be developed.

[0192] Such assays are also applicable to the qualitative orquantitative detection of SET nucleic acid in a sample. Therefore, theinvention thus provides methods for detecting PFM/SET nucleic acid in asample.

[0193] The invention also provides methods for detecting PFM/SETpolypeptide in a sample, by contacting the sample with an agent specificfor PFM/SET, under conditions that allow specific binding of the agentto PFM/SET polypeptide, and detecting the specifically bound agent. Asused herein the term “agent specific for PFM/SET” refers to a moleculethat specifically binds PFM/SET polypeptides. An example of a moleculethat specifically binds PFM or SET is a PFM or SET antibody,respectively, or antigen binding fragment thereof. Additionally, thePFM/SET binding and modulatory compounds identified in the affinityscreening methods described above are also suitable agents that can beused in methods of detecting PFM or SET polypeptides.

[0194] Assays for detecting PFM/SET polypeptides include, for example,immunohistochemistry, immunofluorescence, ELISA assays, radioimmunoassay(RIA), FACS analysis, immunoprecipitation, and immunoblot analysis,using antibodies or antigen binding fragments specific for PFM or SET.Various immunoassays are well known in the art, and can be readilymodified by those skilled in the art in cases in which the agent is aPFM or SET binding molecule other than an antibody. If desired, theagent or antibody can be rendered detectable by incorporation of, or byconjugation to, a detectable moiety, or binding to a secondary moleculethat is itself detectably labeled.

[0195] In the detection methods of the invention, the nucleic acidprobes or primers, and polypeptide binding agents, can advantageously bedirected against the PR domain of PFM, or the A, B or C boxes thereof.Therefore, these assays can be used to distinguish betweenPR+growth-inhibiting, and PR−, growth-promoting, forms of PFM in asample.

[0196] The following examples are intended to illustrate but not limitthe present invention.

[0197] The involvement of PFM/SET in cell differentiation and cancer,and the chromosomal locations of PFM/SET genes, as shown in the Examplesbelow, are consistent with a role for PFM/SET in human diseasesincluding cancer.

EXAMPLE I Identification and Characterization of PFM6

[0198] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM6, and characterizationof its structure and chromosomal location.

[0199] Human genome sequence databases were screened using the PR domainof RIZ1, BLIMP1 and MDS1-EVI1 as probes or queries. This led to theidentification of an unfinished human chromosome 5 genomic sequence(AC010432) encoding a PR domain. Sequence analysis revealed an openreading frame encoding 683 amino acids. The predicted amino acidsequence contains a PR domain, a PKZL domain, and 14 zinc fingerdomains. This gene was designated PFM6 for PR family member 6.

[0200] The PKZL domain stands for “PR and KRAB zinc-finger proteinlinked” domain since the 100 residue domain exhibits 34% identity to theN-terminal region of the KRAB-domain containing zinc finger protein 133,ZNF133.

[0201] The structural features of PFM6 protein suggest a role for theprotein as a DNA binding transcription factor. The PR domain of PFM6 ismore related to PFM4 (GenBank accession number XM_006873) than to otherPR genes.

[0202] Using PFM6 human cDNA as a query sequence, an STS (sequencetagged site) sequence, STS294 was identified. This STS marker maps to5p14. Rearrangements or gains of chromosome 5p are commonly found inovarian and breast cancers (Sonoda et al., (1997) , supra)

EXAMPLE II Identification and Characterization of PFM7

[0203] This example shows identification of the gene encoding thePR-domain containing polypeptide designated PFM7, and characterizationof its structure and chromosomal location.

[0204] cDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. This led to the identification of a partial cDNA sequenceencoding a protein identified as KIAA1231 (GenBank Accession numberAB33057) and a genomic clone on 11q25 (AP000686) that encode a PRdomain. Sequence analysis revealed an open reading frame encoding 1061amino acids. The predicted amino acid sequence contains a PRAZ motif, aPR domain, an acidic motif, and 10 zinc finger motifs. The gene iswidely expressed in adult human tissues. This gene was designated PFM7.

[0205] Using PFM7 human cDNA as a query sequence, a genomic clone(AP000686), which maps to 11q-25, was identified. The chromosomal locus11q25 is frequently deleted in breast, ovary, colon and oral cancer(Connolly et al., supra; Koreth et al., Oncogene 14:431-7 (1997);Launonen et al., supra; Uzawa et al., Intl. J. Cancer 67:510-4 (1996)).It has also been demonstrated that llq25 YAC clones can suppress tumorgrowth in vivo (Koreth et al., Oncogene 18:1157-64 (1999)).

EXAMPLE III Identification and Characterization of PFM8

[0206] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM8, and characterizationof its structure and chromosomal location.

[0207] Human genome sequence databases were screened using the PR domainof RIZ1, BLIMP1 and MDS1-EVI1 as probes or queries. This led to theidentification of an unfinished human chromosome genomic sequence(AC013602) encoding a PR domain. The full length cDNA was obtained byrapid amplification of cDNA ends (RACE) using a Marathon Race Kit(CLONETECH Laboratories, Inc., Palo Alto, Calif.) with a human braincDNA library. The primers used for cloning the PFM CDNA sequence ofabout 0.9 kb were 5′-tgtccctgcacgcccggaagtagatg-3′ (SEQ ID NO:21) and5′-tgtgctggaacgccagcaggtt-3′ (SEQ ID NO:22). The amplified nucleotidesequence is referenced as SEQ ID NO:25. The obtained cDNA encoded a 504amino acid sequence predicted to contain a PR domain and a PRAZ domain.This gene was designated PFM8.

[0208] STS markers within the genomic clone were identified STS markershaving Accession numbers G36915, G37367, G13751, and G52735. The STSmarkers that map 11p11, a region commonly deleted in breast cancer(Nakata et al., supra).

EXAMPLE IV Characterization of PFM9

[0209] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM9, and characterizationof its structure and chromosomal location.

[0210] cDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. This led to the identification of a an unfinished genomic clone(AC015497) encoding a PR domain. Sequence analysis revealed an openreading frame encoding 364 amino acids. The predicted amino acidsequence contains a PR domain and 3 zinc finger motifs. This gene wasdesignated PFM9.

[0211] To map the chromosomal location of PFM9, the Stanford radiationhybrid panel was screened with a pair of PCR primers that amplify PMF9gene. This mapped PFM9 to chromosome 9q33-34.1. This region is commonlydeleted in ovarian, bladder, esophageal, and lung cancers (Devlin etal., supra; Hornigold et al., supra; and Simoneau et al., Oncogene18:157-63 (1999)).

EXAMPLE V Characterization of PFM10

[0212] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM10, and characterizationof its structure and chromosomal location.

[0213] cDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. This led to the identification of a an unfinished genomic cloneon chromosome 6q16.1-21 (AL035087) encoding a PR domain. Sequenceanalysis revealed an open reading frame encoding 717 amino acids. Thepredicted amino acid sequence contains a PR motif and 4 zinc fingermotifs.

[0214] To map the chromosomal location of PFM10, the Stanford radiationhybrid panel was screened with a pair of PCR primers that amplify PMF10gene. This mapped PFM10 to chromosome 6q16-21. The 6q16-21 region iscommonly deleted in B-cell lymphoma, melanoma, and stomach cancers. Thisregion also contains another PR-family member, the candidate tumorsuppressor PRDIBF1/BLIMP1 (PRDM1) (Mock et al., supra).

EXAMPLE VI Characterization of PFM11

[0215] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM11, and characterizationof its structure and chromosomal location.

[0216] cDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. This led to the identification of a genomic clone (AC018740)that encodes a PR domain. Sequence analysis revealed an open readingframe encoding 518 amino acids. The predicted amino acid sequencecontains a PR domain.

[0217] To map the chromosomal location of PFM11, the Stanford radiationhybrid panel was screened with a pair of PCR primers that amplify PMF11gene. This mapped PFM11to chromosome 8p12-21, a region commonly deletedin breast and prostate cancers (Van Alewijk et al., Genes, Chromosomes &Cancer 24:119-26 (1999); Verma et al., supra; and Vocke et al., supra).

EXAMPLE VII Characterization of PFM12

[0218] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM12, and characterizationof its structure and chromosomal location.

[0219] CDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. This led to the identification of a sequence on chromosome 21that encodes a PR domain. Sequence analysis revealed an open readingframe encoding 951 amino acids. The predicted amino acid sequencecontains a PR domain, PRAZ motif and 8 C2H2 zinc finger domains.

[0220] To map the chromosomal location of PFM12, the Stanford radiationhybrid panel was screened with a pair of PCR primers that amplify PMF12.This mapped PFM12 to chromosome 21q22.3, a region deleted in humanleukemia (Hoffman et al. Annals of Oncology, 6(8):781-8 (1995),Pederson-Bjergaard et al. Leukemia, 7(12):1975- 86 (1993) and Rubin etal. Blood, 76(12):2594-8 (1990)) and bladder cancer (Babu et al. CancerGenetics and Cytogenetics 38(1):127-9 (1989)).

EXAMPLE VIII Characterization of PFM13

[0221] This example shows identification of the gene encoding thePR−domain containing polypeptide designated PFM13, and characterizationof its structure and chromosomal location.

[0222] cDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. An EST clone (AI278689) was initially identified having apartial PR domain. Sequence of the cDNA was obtained by RACE, asdescribed above in relation to PFM8, and by analysis of sequences in thepublic databases. The primers used for amplifying the PFM13 cDNA were5′-gggggtagacgccttggttcacg-3′ (SEQ ID NO:23), and5′-catcgcaggagcacgccacac-3′ (SEQ ID NO:24). The amplified nucleotidesequence is referenced as SEQ ID NO:26. The full length cDNA of 4367 bpis predicted to encode 1257 amino acids. The predicted amino acidsequence contains a PR domain and 10 zinc finger domains. The sequenceshares 51% peptide sequence identity with the MDS1-EVI1 cancer gene overthe entire length of the protein, and is therefore a paralog ofMDS1-EVI1.

[0223] By STS content mapping, the PFM13 gene was mapped to chromosomeband 1p36.23-33, a region deleted in more than a dozen different typesof human cancers. The proven role of MDS1-EVI1 and RIZ1 (also on 1p36)in human cancers (Huang, 1999), suggests a role for PFM13 as one ofseveral tumor suppressors thought to reside on 1p36.

EXAMPLE IX Characterization of PFM14

[0224] This example shows identification of the gene encoding thePR-domain containing polypeptide designated PFM14, and characterizationof its structure and chromosomal location.

[0225] cDNA libraries and human genomic sequence libraries werescreening using the PR domain of RIZ1, BLIMP1 and MDS1-EVI1 as probes orqueries. An EST clone (BE732157.1) was initially identified having apartial PR domain. The EST clone was used to identify a genomic sequence(AC12054) on chromosome 11, which was then used to predict an openreading frame of 720 amino acids. The predicted amino acid sequence ofPFM14 contains one PR domain and 10 zinc finger motifs.

EXAMPLE X Characterization of SET07

[0226] This example shows identification of the gene encoding theSET-domain containing polypeptide designated SET07, and characterizationof its structure and chromosomal location.

[0227] cDNA libraries and human genomic sequence libraries werescreening using the SET domain of human HRX as a query. An EST clone(AA085455) was found to contain a SET domain. A full length cDNAcontaining the SET domain was assembled using sequences in the publicdatabases. A genomic sequence (AC005283) was identified to contain theSET domain gene, termed SET07. An STS identified to correspond to thegenomic sequence was used to map SET07 to chromosome 13q11-q13, inproximity to the retinoblastoma locus on 13q14. This region is commonlydeleted in many cancers including breast cancers, bladder cancers, lungcancers and osteosarcomas.

EXAMPLE XI PFM/SET Modulation of Cell Proliferation

[0228] This Example describes a method for demonstrating the ability ofa PFM/SET nucleic acid to modulate cell proliferation.

[0229] A human PFM/SET cDNA is inserted into a mammalian expressionvector, such as pCMV-Tag4, to generate an expression construct encodingPFM/SET. The encoded PFM/SET polypeptide can be tagged with a detectableepitope, for example, with a myc, GST or FLAG epitope tag, at theC-terminus. Alternatively, the desired epitope can be placed at theN-terminus, or at an internal site, so long as the epitope does notinterfere with PFM/SET activity. The PFM/SET expression construct istransfected, either transiently or stably, into cells (for example, 293or NIH-3T3 cells) using a commercially available reagent, such asEffectene or Superfect transfection reagents (Qiagen, Valencia, Calif.).Expression of the PFM/SET protein from the construct is then confirmedby detecting the epitope or the PFM/SET polypeptide, for example, byimmunostaining of cells or immunoblot analysis.

[0230] Cell proliferation in cells having or lacking PFM/SET expressionis then determined. One well known method for measuring cellproliferation is by measuring BrdU incorporation. BrdU incorporationinto DNA is a measure of DNA synthesis, which is required for cellproliferation. The effect of PFM/SET expression on cell proliferation ismeasured by growing cells for 2 h in BrdU-containing media followingtransfection, staining the cells with anti-BrdU monoclonal antibody andDAPI (nuclear staining reagent), and counting the number of BrdUpositive and negative cells in several different microscopic views.

[0231] In this manner, the effect of PFM/SET expression on cellproliferation can be determined. A variety of other cell proliferationassays are well known to those skilled in the art, and can also be usedfor determining cell proliferation in cells lacking or expressing aPFM/SET polypeptide.

[0232] All journal article, reference and patent citations providedabove, including referenced sequence accession numbers of nucleotide andamino acid sequences contained in various databases, in parentheses orotherwise, whether previously stated or not, are incorporated herein byreference in their entirety.

[0233] Although the invention has been described with reference to theexamples provided above, it should be understood that variousmodifications can be made without departing from the spirit of theinvention.

1 33 1 2903 DNA Homo sapiens CDS (10)...(2076) 1 gattgtgag atg tgt cagaac ttc ttc att gac agc tgt gct gcc cat ggg 51 Met Cys Gln Asn Phe PheIle Asp Ser Cys Ala Ala His Gly 1 5 10 ccc cct aca ttt gta aag gac agtgca gtg gac aag ggg cac ccc aac 99 Pro Pro Thr Phe Val Lys Asp Ser AlaVal Asp Lys Gly His Pro Asn 15 20 25 30 cgt tca gcc ctc agt ctg ccc ccaggg ctg aga att ggg cca tca ggc 147 Arg Ser Ala Leu Ser Leu Pro Pro GlyLeu Arg Ile Gly Pro Ser Gly 35 40 45 atc cct cag gct ggg ctt gga gta tggaat gag gca tct gat ctg ccg 195 Ile Pro Gln Ala Gly Leu Gly Val Trp AsnGlu Ala Ser Asp Leu Pro 50 55 60 ctg ggt ctg cac ttt ggc cct tat gag ggccga att aca gaa gac gaa 243 Leu Gly Leu His Phe Gly Pro Tyr Glu Gly ArgIle Thr Glu Asp Glu 65 70 75 gag gca gcc aac aat gga tac tcc tgg ctg gtaaga aga gcc tgc cat 291 Glu Ala Ala Asn Asn Gly Tyr Ser Trp Leu Val ArgArg Ala Cys His 80 85 90 ttc acc aag ggg aga aac tgc tat gag tat gtg gatgga aaa gat aaa 339 Phe Thr Lys Gly Arg Asn Cys Tyr Glu Tyr Val Asp GlyLys Asp Lys 95 100 105 110 tcc tgg gcc aac tgg atg agg tat gtg aac tgtgcc cgg gat gat gaa 387 Ser Trp Ala Asn Trp Met Arg Tyr Val Asn Cys AlaArg Asp Asp Glu 115 120 125 gag cag aac ctg gtg gcc ttc cag tac cac aggcag atc ttc tat aga 435 Glu Gln Asn Leu Val Ala Phe Gln Tyr His Arg GlnIle Phe Tyr Arg 130 135 140 acc tgc cga gtc att agg cca ggc tgt gaa ctgctg gtc tgg tat ggg 483 Thr Cys Arg Val Ile Arg Pro Gly Cys Glu Leu LeuVal Trp Tyr Gly 145 150 155 gat gaa tac ggc cag gaa ctg ggc atc aag tggggc agc aag tgg aag 531 Asp Glu Tyr Gly Gln Glu Leu Gly Ile Lys Trp GlySer Lys Trp Lys 160 165 170 aaa gag gaa cca aag cca gag atc cat cca tgtccc tca tgc tgt ctg 579 Lys Glu Glu Pro Lys Pro Glu Ile His Pro Cys ProSer Cys Cys Leu 175 180 185 190 gcc ttt tca agt cag aaa ttt ctc agt caacat gta gaa cgc aat cac 627 Ala Phe Ser Ser Gln Lys Phe Leu Ser Gln HisVal Glu Arg Asn His 195 200 205 tcc tct cag aac ttc cca gga cca tct gcaaga aaa ctc ctc caa cca 675 Ser Ser Gln Asn Phe Pro Gly Pro Ser Ala ArgLys Leu Leu Gln Pro 210 215 220 gag aat ccc tgc cca ggg gat cag aat caggag cag caa tat cca gat 723 Glu Asn Pro Cys Pro Gly Asp Gln Asn Gln GluGln Gln Tyr Pro Asp 225 230 235 cca cac agc cgt aat gac aaa acc aaa ggtcaa gag atc aaa gaa agg 771 Pro His Ser Arg Asn Asp Lys Thr Lys Gly GlnGlu Ile Lys Glu Arg 240 245 250 tcc aaa ctc ttg aat aaa agg aca tgg cagagg gag att tca agg gcc 819 Ser Lys Leu Leu Asn Lys Arg Thr Trp Gln ArgGlu Ile Ser Arg Ala 255 260 265 270 ttt tct agc cca ccc aaa gga caa atgggg agc tgt aga gtg gga aaa 867 Phe Ser Ser Pro Pro Lys Gly Gln Met GlySer Cys Arg Val Gly Lys 275 280 285 aga ata atg gaa gaa gag tcc aga acaggc cag aaa gtg aat cca ggg 915 Arg Ile Met Glu Glu Glu Ser Arg Thr GlyGln Lys Val Asn Pro Gly 290 295 300 aac aca ggc aaa tta ttt gtg ggg gtagga atc tca aga att gca aaa 963 Asn Thr Gly Lys Leu Phe Val Gly Val GlyIle Ser Arg Ile Ala Lys 305 310 315 gtc aag tat gga gag tgt gga caa ggtttc agt gtt aaa tca gat gtt 1011 Val Lys Tyr Gly Glu Cys Gly Gln Gly PheSer Val Lys Ser Asp Val 320 325 330 att aca cac caa agg aca cat aca ggggag aag ctc tac gtc tgc agg 1059 Ile Thr His Gln Arg Thr His Thr Gly GluLys Leu Tyr Val Cys Arg 335 340 345 350 gag tgt ggg cgg ggc ttt agc tggaag tca cac ctc ctc att cac cag 1107 Glu Cys Gly Arg Gly Phe Ser Trp LysSer His Leu Leu Ile His Gln 355 360 365 agg ata cac aca ggg gag aag ccctat gtc tgc agg gag tgt ggg cgg 1155 Arg Ile His Thr Gly Glu Lys Pro TyrVal Cys Arg Glu Cys Gly Arg 370 375 380 ggc ttt agc tgg cag tca gtc ctcctc act cac cag agg aca cac aca 1203 Gly Phe Ser Trp Gln Ser Val Leu LeuThr His Gln Arg Thr His Thr 385 390 395 ggg gag aag ccc tat gtc tgc agggag tgt ggg cgg ggc ttt agc cgg 1251 Gly Glu Lys Pro Tyr Val Cys Arg GluCys Gly Arg Gly Phe Ser Arg 400 405 410 cag tca gtc ctc ctc act cac cagagg aga cac aca ggg gag aag ccc 1299 Gln Ser Val Leu Leu Thr His Gln ArgArg His Thr Gly Glu Lys Pro 415 420 425 430 tat gtc tgc agg gag tgt gggcgg ggc ttt agc cgg cag tca gtc ctc 1347 Tyr Val Cys Arg Glu Cys Gly ArgGly Phe Ser Arg Gln Ser Val Leu 435 440 445 ctc act cac cag agg aga cacaca ggg gag aag ccc tat gtc tgc agg 1395 Leu Thr His Gln Arg Arg His ThrGly Glu Lys Pro Tyr Val Cys Arg 450 455 460 gag tgt ggg cgg ggc ttt agctgg cag tca gtc ctc ctc act cac cag 1443 Glu Cys Gly Arg Gly Phe Ser TrpGln Ser Val Leu Leu Thr His Gln 465 470 475 agg aca cac aca ggg gag aagccc tat gtc tgc agg gag tgt ggg cgg 1491 Arg Thr His Thr Gly Glu Lys ProTyr Val Cys Arg Glu Cys Gly Arg 480 485 490 ggc ttt agc tgg cag tca gtcctc ctc act cac cag agg aca cac aca 1539 Gly Phe Ser Trp Gln Ser Val LeuLeu Thr His Gln Arg Thr His Thr 495 500 505 510 ggg gag aag ccc tat gtctgc agg gag tgt ggg cgg ggc ttt agc aat 1587 Gly Glu Lys Pro Tyr Val CysArg Glu Cys Gly Arg Gly Phe Ser Asn 515 520 525 aag tca cac ctc ctc agacac cag agg aca cac aca ggg gag aag ccc 1635 Lys Ser His Leu Leu Arg HisGln Arg Thr His Thr Gly Glu Lys Pro 530 535 540 tat gtc tgc agg gag tgtggg cgg ggc ttt cgc gat aag tca cac ctc 1683 Tyr Val Cys Arg Glu Cys GlyArg Gly Phe Arg Asp Lys Ser His Leu 545 550 555 ctc aga cac cag agg acacac aca ggg gag aag ccc tat gtc tgc agg 1731 Leu Arg His Gln Arg Thr HisThr Gly Glu Lys Pro Tyr Val Cys Arg 560 565 570 gag tgt ggg cgg ggc tttaga gat aag tca aac ctc ctc agt cac cag 1779 Glu Cys Gly Arg Gly Phe ArgAsp Lys Ser Asn Leu Leu Ser His Gln 575 580 585 590 agg aca cac aca ggggag aag ccc tat gtc tgc agg gag tgt ggg cgg 1827 Arg Thr His Thr Gly GluLys Pro Tyr Val Cys Arg Glu Cys Gly Arg 595 600 605 ggc ttt agc aat aagtca cac ctc ctc aga cac cag agg aca cac aca 1875 Gly Phe Ser Asn Lys SerHis Leu Leu Arg His Gln Arg Thr His Thr 610 615 620 ggg gag aag ccc tatgtc tgc agg gag tgt ggg cgg ggc ttt cgc aat 1923 Gly Glu Lys Pro Tyr ValCys Arg Glu Cys Gly Arg Gly Phe Arg Asn 625 630 635 aag tca cac ctc ctcaga cac cag agg aca cac aca ggg gag aag ccc 1971 Lys Ser His Leu Leu ArgHis Gln Arg Thr His Thr Gly Glu Lys Pro 640 645 650 tac gtc tgc agg gagtgt ggg cgg ggc ttt agc gat agg tca agc ctc 2019 Tyr Val Cys Arg Glu CysGly Arg Gly Phe Ser Asp Arg Ser Ser Leu 655 660 665 670 tgc tat cac cagagg aca cac aca ggg gag aag ccc tac gtc tgc agg 2067 Cys Tyr His Gln ArgThr His Thr Gly Glu Lys Pro Tyr Val Cys Arg 675 680 685 gag gat gagtaagtcatta gtaataaaac ctcatctcaa tagccacaaa 2116 Glu Asp Glu aagacaaatgtggtcaccac acacttgcac accccagctg tgaggtggct tcagcggaag 2176 tctgctgaccccttatattc cccgagagta taaagagatc ggaaataact gattaaacaa 2236 atccgccactttcatgacta gagatgagga agaacaaggg atagttctgt aagtgttcgg 2296 gggacatcagcatgtgtggt tctttcccgc actgatcccc tccatttttt gtttgttttt 2356 ttgcctcctgttctaataaa ttttgtctcc atacaaatct gaaccccaag tgtgtacctc 2416 attcttcccttatcactgaa ggcaagaaga gtccagaagg gccacagaga actcatgtgt 2476 tcagctcaagactccacagg aattcaaccc ccagaaagac ataaacttgg agtccgtctg 2536 gtttaattattggagaatcg attcccaagt ccaggaagag aaatgtaaga ttctagaaag 2596 tcgcagcaggaaagggagtt ccctggtctc ctgggaagtg tggcttcttc tcctaatgga 2656 cacctctcctctgctgccat actctccctt ggctccccag tctcctctcc tgatctcctc 2716 caatctctgtagcccaagat gtgaaagcca gacaagaaca cgcgtgtgtg tatatatgtg 2776 ttcgggtgtgggggtatgtg ccctccgtgt aggtaactgt gtgagtgtgg ggggtttcaa 2836 gggtgtgttaggaacaacgc tcaaaatcct aaggaaactg aacactcgaa cgaaggattc 2896 ttagcaa 29032 689 PRT Homo sapiens 2 Met Cys Gln Asn Phe Phe Ile Asp Ser Cys Ala AlaHis Gly Pro Pro 1 5 10 15 Thr Phe Val Lys Asp Ser Ala Val Asp Lys GlyHis Pro Asn Arg Ser 20 25 30 Ala Leu Ser Leu Pro Pro Gly Leu Arg Ile GlyPro Ser Gly Ile Pro 35 40 45 Gln Ala Gly Leu Gly Val Trp Asn Glu Ala SerAsp Leu Pro Leu Gly 50 55 60 Leu His Phe Gly Pro Tyr Glu Gly Arg Ile ThrGlu Asp Glu Glu Ala 65 70 75 80 Ala Asn Asn Gly Tyr Ser Trp Leu Val ArgArg Ala Cys His Phe Thr 85 90 95 Lys Gly Arg Asn Cys Tyr Glu Tyr Val AspGly Lys Asp Lys Ser Trp 100 105 110 Ala Asn Trp Met Arg Tyr Val Asn CysAla Arg Asp Asp Glu Glu Gln 115 120 125 Asn Leu Val Ala Phe Gln Tyr HisArg Gln Ile Phe Tyr Arg Thr Cys 130 135 140 Arg Val Ile Arg Pro Gly CysGlu Leu Leu Val Trp Tyr Gly Asp Glu 145 150 155 160 Tyr Gly Gln Glu LeuGly Ile Lys Trp Gly Ser Lys Trp Lys Lys Glu 165 170 175 Glu Pro Lys ProGlu Ile His Pro Cys Pro Ser Cys Cys Leu Ala Phe 180 185 190 Ser Ser GlnLys Phe Leu Ser Gln His Val Glu Arg Asn His Ser Ser 195 200 205 Gln AsnPhe Pro Gly Pro Ser Ala Arg Lys Leu Leu Gln Pro Glu Asn 210 215 220 ProCys Pro Gly Asp Gln Asn Gln Glu Gln Gln Tyr Pro Asp Pro His 225 230 235240 Ser Arg Asn Asp Lys Thr Lys Gly Gln Glu Ile Lys Glu Arg Ser Lys 245250 255 Leu Leu Asn Lys Arg Thr Trp Gln Arg Glu Ile Ser Arg Ala Phe Ser260 265 270 Ser Pro Pro Lys Gly Gln Met Gly Ser Cys Arg Val Gly Lys ArgIle 275 280 285 Met Glu Glu Glu Ser Arg Thr Gly Gln Lys Val Asn Pro GlyAsn Thr 290 295 300 Gly Lys Leu Phe Val Gly Val Gly Ile Ser Arg Ile AlaLys Val Lys 305 310 315 320 Tyr Gly Glu Cys Gly Gln Gly Phe Ser Val LysSer Asp Val Ile Thr 325 330 335 His Gln Arg Thr His Thr Gly Glu Lys LeuTyr Val Cys Arg Glu Cys 340 345 350 Gly Arg Gly Phe Ser Trp Lys Ser HisLeu Leu Ile His Gln Arg Ile 355 360 365 His Thr Gly Glu Lys Pro Tyr ValCys Arg Glu Cys Gly Arg Gly Phe 370 375 380 Ser Trp Gln Ser Val Leu LeuThr His Gln Arg Thr His Thr Gly Glu 385 390 395 400 Lys Pro Tyr Val CysArg Glu Cys Gly Arg Gly Phe Ser Arg Gln Ser 405 410 415 Val Leu Leu ThrHis Gln Arg Arg His Thr Gly Glu Lys Pro Tyr Val 420 425 430 Cys Arg GluCys Gly Arg Gly Phe Ser Arg Gln Ser Val Leu Leu Thr 435 440 445 His GlnArg Arg His Thr Gly Glu Lys Pro Tyr Val Cys Arg Glu Cys 450 455 460 GlyArg Gly Phe Ser Trp Gln Ser Val Leu Leu Thr His Gln Arg Thr 465 470 475480 His Thr Gly Glu Lys Pro Tyr Val Cys Arg Glu Cys Gly Arg Gly Phe 485490 495 Ser Trp Gln Ser Val Leu Leu Thr His Gln Arg Thr His Thr Gly Glu500 505 510 Lys Pro Tyr Val Cys Arg Glu Cys Gly Arg Gly Phe Ser Asn LysSer 515 520 525 His Leu Leu Arg His Gln Arg Thr His Thr Gly Glu Lys ProTyr Val 530 535 540 Cys Arg Glu Cys Gly Arg Gly Phe Arg Asp Lys Ser HisLeu Leu Arg 545 550 555 560 His Gln Arg Thr His Thr Gly Glu Lys Pro TyrVal Cys Arg Glu Cys 565 570 575 Gly Arg Gly Phe Arg Asp Lys Ser Asn LeuLeu Ser His Gln Arg Thr 580 585 590 His Thr Gly Glu Lys Pro Tyr Val CysArg Glu Cys Gly Arg Gly Phe 595 600 605 Ser Asn Lys Ser His Leu Leu ArgHis Gln Arg Thr His Thr Gly Glu 610 615 620 Lys Pro Tyr Val Cys Arg GluCys Gly Arg Gly Phe Arg Asn Lys Ser 625 630 635 640 His Leu Leu Arg HisGln Arg Thr His Thr Gly Glu Lys Pro Tyr Val 645 650 655 Cys Arg Glu CysGly Arg Gly Phe Ser Asp Arg Ser Ser Leu Cys Tyr 660 665 670 His Gln ArgThr His Thr Gly Glu Lys Pro Tyr Val Cys Arg Glu Asp 675 680 685 Glu 36010 DNA Homo sapiens CDS (217)...(3399) 3 agccctccca ggtgtgggacagaaggggca gagggagggc agaggcttaa aggctgtgag 60 cagtcagatc aaaaatgaagccagctcttc ctcacagccg gtagatggaa gtcatttttc 120 cagggcctgg aaggagttggtaggaagact agatttcagc cagcccttgc gccctgtttg 180 tgccagcagg caccagcgaaccaaaagcag gtgtcc atg tct gct tac tct gtg 234 Met Ser Ala Tyr Ser Val 15 cct tca act ttt gcc cag gcc tca ttg cca gtt cat aac cag gtg ctg 282Pro Ser Thr Phe Ala Gln Ala Ser Leu Pro Val His Asn Gln Val Leu 10 15 20cct tcc atc gag agt gta gat ggg tcc gac cct ttg gca act ctg cag 330 ProSer Ile Glu Ser Val Asp Gly Ser Asp Pro Leu Ala Thr Leu Gln 25 30 35 acccct cta ggc aga ctg gag gcc aaa gag gaa gag gat gag gat gag 378 Thr ProLeu Gly Arg Leu Glu Ala Lys Glu Glu Glu Asp Glu Asp Glu 40 45 50 gac gaggac act gag gaa gat gag gaa gaa gac ggt gag gac acg gat 426 Asp Glu AspThr Glu Glu Asp Glu Glu Glu Asp Gly Glu Asp Thr Asp 55 60 65 70 ctg gatgac tgg gag cca gac ccg ccc cgg ccc ttc gac cca cac gac 474 Leu Asp AspTrp Glu Pro Asp Pro Pro Arg Pro Phe Asp Pro His Asp 75 80 85 ttg tgg tgtgag gag tgc aat aac gcg cat gct tca gtg tgt ccg aag 522 Leu Trp Cys GluGlu Cys Asn Asn Ala His Ala Ser Val Cys Pro Lys 90 95 100 cac ggc cccttg cac ccg atc ccc aac cgg ccg gtg ctc acc cgg gcc 570 His Gly Pro LeuHis Pro Ile Pro Asn Arg Pro Val Leu Thr Arg Ala 105 110 115 agg gcg agcctc ccc ctg gtg ctc tac ata gac agg ttt ctg ggc ggg 618 Arg Ala Ser LeuPro Leu Val Leu Tyr Ile Asp Arg Phe Leu Gly Gly 120 125 130 gtg ttc tccaag cgg cgc atc ccc aag cgc acc cag ttt ggc ccc gtg 666 Val Phe Ser LysArg Arg Ile Pro Lys Arg Thr Gln Phe Gly Pro Val 135 140 145 150 gag gggcct ctc gtc agg ggc tcg gag ctg aaa gac tgt tac att cac 714 Glu Gly ProLeu Val Arg Gly Ser Glu Leu Lys Asp Cys Tyr Ile His 155 160 165 ctc aaggtt tct ctt gat aaa ggg gac agg aaa gaa agg gat tta cat 762 Leu Lys ValSer Leu Asp Lys Gly Asp Arg Lys Glu Arg Asp Leu His 170 175 180 gaa gaccta tgg ttt gag ttg tct gat gag acg ctt tgt aac tgg atg 810 Glu Asp LeuTrp Phe Glu Leu Ser Asp Glu Thr Leu Cys Asn Trp Met 185 190 195 atg tttgta cgg cca gcc cag aat cac ctg gag cag aac ctg gtg gct 858 Met Phe ValArg Pro Ala Gln Asn His Leu Glu Gln Asn Leu Val Ala 200 205 210 tac cagtat ggc cac cat gtg tat tat aca acc ata aaa aat gtg gag 906 Tyr Gln TyrGly His His Val Tyr Tyr Thr Thr Ile Lys Asn Val Glu 215 220 225 230 cccaag cag gaa ctg aag gtg tgg tat gcc gca tcc tat gct gag ttc 954 Pro LysGln Glu Leu Lys Val Trp Tyr Ala Ala Ser Tyr Ala Glu Phe 235 240 245 gtgaac cag aaa att cat gac att tct gag gaa gaa agg aaa gtt ctt 1002 Val AsnGln Lys Ile His Asp Ile Ser Glu Glu Glu Arg Lys Val Leu 250 255 260 cgagag caa gag aag aat tgg ccc tgc tat gaa tgt aac cgc cga ttt 1050 Arg GluGln Glu Lys Asn Trp Pro Cys Tyr Glu Cys Asn Arg Arg Phe 265 270 275 ataagc tcg gag cag ttg caa cag cat ctc aat tct cat gat gag aaa 1098 Ile SerSer Glu Gln Leu Gln Gln His Leu Asn Ser His Asp Glu Lys 280 285 290 ctagat gtg ttt agc aga aca aga ggc aga gga agg gga cga ggc aag 1146 Leu AspVal Phe Ser Arg Thr Arg Gly Arg Gly Arg Gly Arg Gly Lys 295 300 305 310agg cga ttc ggt cca ggt cga cgg ccg ggg cgt cct cca aaa ttt atc 1194 ArgArg Phe Gly Pro Gly Arg Arg Pro Gly Arg Pro Pro Lys Phe Ile 315 320 325cgc ctg gaa atc acc agc gaa aat ggg gaa aag agt gac gat ggg aca 1242 ArgLeu Glu Ile Thr Ser Glu Asn Gly Glu Lys Ser Asp Asp Gly Thr 330 335 340cag gac ttg cta cat ttt ccc aca aag gag caa ttt gat gag gct gaa 1290 GlnAsp Leu Leu His Phe Pro Thr Lys Glu Gln Phe Asp Glu Ala Glu 345 350 355cca gcc act ctg aat ggg ctg gat caa cca gaa cag acc act atc cca 1338 ProAla Thr Leu Asn Gly Leu Asp Gln Pro Glu Gln Thr Thr Ile Pro 360 365 370atc cct cag ctg cca cag gaa acc cag tct tcc ctg gaa cat gaa cca 1386 IlePro Gln Leu Pro Gln Glu Thr Gln Ser Ser Leu Glu His Glu Pro 375 380 385390 gaa act cac acc ctg cac ctg cag ccg cag cat gaa gag agc gtg gtg 1434Glu Thr His Thr Leu His Leu Gln Pro Gln His Glu Glu Ser Val Val 395 400405 ccc acc cag agc acg ctg aca gcc gac gac atg cgc aga gcc aag cgc 1482Pro Thr Gln Ser Thr Leu Thr Ala Asp Asp Met Arg Arg Ala Lys Arg 410 415420 atc cga ttg gag ctg cag aat gca gct ctt cag cat ctg ttt att cgg 1530Ile Arg Leu Glu Leu Gln Asn Ala Ala Leu Gln His Leu Phe Ile Arg 425 430435 aag tcc ttc cgg cct ttt aaa tgc ttg cag tgt ggg aag gcc ttc cgg 1578Lys Ser Phe Arg Pro Phe Lys Cys Leu Gln Cys Gly Lys Ala Phe Arg 440 445450 gaa aag gac aaa ctg gac cag cac tta cgc ttc cat ggg cgg gag ggg 1626Glu Lys Asp Lys Leu Asp Gln His Leu Arg Phe His Gly Arg Glu Gly 455 460465 470 aac tgc cca ctg acc tgt gat ctc tgt aac aag ggc ttc atc agc agc1674 Asn Cys Pro Leu Thr Cys Asp Leu Cys Asn Lys Gly Phe Ile Ser Ser 475480 485 aca tcc ttg gag agc cac atg aag ctc cac tca gac cag aag act tac1722 Thr Ser Leu Glu Ser His Met Lys Leu His Ser Asp Gln Lys Thr Tyr 490495 500 tct tgc att ttt tgc cca gaa tcc ttt gac cgc ctt gat ttg ttg aaa1770 Ser Cys Ile Phe Cys Pro Glu Ser Phe Asp Arg Leu Asp Leu Leu Lys 505510 515 gat cat gtg gcc att cat atc aat gat ggc tac ttc acc tgc cca act1818 Asp His Val Ala Ile His Ile Asn Asp Gly Tyr Phe Thr Cys Pro Thr 520525 530 tgt aag aaa cgg ttc cca gat ttt atc cag gtg aaa aaa cac gtg cgc1866 Cys Lys Lys Arg Phe Pro Asp Phe Ile Gln Val Lys Lys His Val Arg 535540 545 550 agc ttc cac tca gaa aag atc tac cag tgc aca gag tgt gac aaggcc 1914 Ser Phe His Ser Glu Lys Ile Tyr Gln Cys Thr Glu Cys Asp Lys Ala555 560 565 ttc tgt cgc ccc gat aaa ctg cga ctc cac atg ctc cgg cat tcggac 1962 Phe Cys Arg Pro Asp Lys Leu Arg Leu His Met Leu Arg His Ser Asp570 575 580 cgc aaa gac ttc ctg tgt tcc acc tgt ggg aag caa ttt aag cgaaaa 2010 Arg Lys Asp Phe Leu Cys Ser Thr Cys Gly Lys Gln Phe Lys Arg Lys585 590 595 gac aaa cta cgg gaa cac atg cag agg atg cat aat cct gag agggag 2058 Asp Lys Leu Arg Glu His Met Gln Arg Met His Asn Pro Glu Arg Glu600 605 610 gcc aag aaa gcc gac cgc atc agc cgc tcc aag acg ttc aag ccccgc 2106 Ala Lys Lys Ala Asp Arg Ile Ser Arg Ser Lys Thr Phe Lys Pro Arg615 620 625 630 atc acg tcc aca gac tac gac agc ttc acg ttc aag tgc cgcctg tgc 2154 Ile Thr Ser Thr Asp Tyr Asp Ser Phe Thr Phe Lys Cys Arg LeuCys 635 640 645 atg atg ggc ttc cgg cgg cgc ggc atg ctg gta aat cac ttatcg aag 2202 Met Met Gly Phe Arg Arg Arg Gly Met Leu Val Asn His Leu SerLys 650 655 660 aga cac cca gac atg aag ata gaa gag gtg cca gag tta actcta ccc 2250 Arg His Pro Asp Met Lys Ile Glu Glu Val Pro Glu Leu Thr LeuPro 665 670 675 atc ata aaa ccc aat cgt gat tac ttt tgt cag tat tgc gataag gtt 2298 Ile Ile Lys Pro Asn Arg Asp Tyr Phe Cys Gln Tyr Cys Asp LysVal 680 685 690 tat aaa agt gcc agc aag cgc aaa gcc cac att ctg aag aaccac cca 2346 Tyr Lys Ser Ala Ser Lys Arg Lys Ala His Ile Leu Lys Asn HisPro 695 700 705 710 gga gca gag ctc cca ccg agc att cgg aag ctc cga cccgct ggt cct 2394 Gly Ala Glu Leu Pro Pro Ser Ile Arg Lys Leu Arg Pro AlaGly Pro 715 720 725 gga gag cca gac ccc atg ctg agc aca cac acc cag ctgacg ggc acc 2442 Gly Glu Pro Asp Pro Met Leu Ser Thr His Thr Gln Leu ThrGly Thr 730 735 740 atc gcc acc cct ccc gtc tgc tgt ccc cac tgc tcc aagcag tac agc 2490 Ile Ala Thr Pro Pro Val Cys Cys Pro His Cys Ser Lys GlnTyr Ser 745 750 755 agc aag acc aag atg gtc cag cac att cga aag aag catcca gag ttc 2538 Ser Lys Thr Lys Met Val Gln His Ile Arg Lys Lys His ProGlu Phe 760 765 770 gcc cag ctc tcc aac acc ata cac aca cca ctg acg acagct gtg atc 2586 Ala Gln Leu Ser Asn Thr Ile His Thr Pro Leu Thr Thr AlaVal Ile 775 780 785 790 agt gcc acc cca gcg gtt ttg act aca gac agc gccact gga gag act 2634 Ser Ala Thr Pro Ala Val Leu Thr Thr Asp Ser Ala ThrGly Glu Thr 795 800 805 gtg gtg acg acg gac ctg ctc acc caa gca atg acagaa ctg tcc cag 2682 Val Val Thr Thr Asp Leu Leu Thr Gln Ala Met Thr GluLeu Ser Gln 810 815 820 acc tta acg aca gac tac cga acg cca caa ggg gattac cag aga att 2730 Thr Leu Thr Thr Asp Tyr Arg Thr Pro Gln Gly Asp TyrGln Arg Ile 825 830 835 cag tac atc cct gtg tcg cag tcg gcg tct ggc ctccag cag cct cag 2778 Gln Tyr Ile Pro Val Ser Gln Ser Ala Ser Gly Leu GlnGln Pro Gln 840 845 850 cac ata cag ctg caa gtg gtt caa gtg gcc tcg gccact tcc cct cac 2826 His Ile Gln Leu Gln Val Val Gln Val Ala Ser Ala ThrSer Pro His 855 860 865 870 cag tca cag cag tcc act gtg gat gtt ggc cagctc cat gat cct cag 2874 Gln Ser Gln Gln Ser Thr Val Asp Val Gly Gln LeuHis Asp Pro Gln 875 880 885 ccc tac ccc cag cac gcc atc cag gtg cag cacatc cag gta tct ggg 2922 Pro Tyr Pro Gln His Ala Ile Gln Val Gln His IleGln Val Ser Gly 890 895 900 cag ccg ttg agt ccc tca gcc cag cag gct cagcag ggg ctc agc ccc 2970 Gln Pro Leu Ser Pro Ser Ala Gln Gln Ala Gln GlnGly Leu Ser Pro 905 910 915 tcc cac atc cag ggc agt tct tcc aca cag gggcag gct ctg cag cag 3018 Ser His Ile Gln Gly Ser Ser Ser Thr Gln Gly GlnAla Leu Gln Gln 920 925 930 cag cag cag cag cag cag aat tcc tct gtg cagcac acg tac ctg ccc 3066 Gln Gln Gln Gln Gln Gln Asn Ser Ser Val Gln HisThr Tyr Leu Pro 935 940 945 950 agt gct tgg aat tcc ttc cgt ggc tat tcatct gag att caa atg atg 3114 Ser Ala Trp Asn Ser Phe Arg Gly Tyr Ser SerGlu Ile Gln Met Met 955 960 965 acg ctt cct ccg ggt cag ttt gtg att acagac agt ggt gtg gca act 3162 Thr Leu Pro Pro Gly Gln Phe Val Ile Thr AspSer Gly Val Ala Thr 970 975 980 cca gtt act act ggc cag gtg aag gcg gttact tcg ggt cat tat gtg 3210 Pro Val Thr Thr Gly Gln Val Lys Ala Val ThrSer Gly His Tyr Val 985 990 995 tta tca gaa agt caa tca gaa ttg gaa gaaaag caa act tct gcc ctc 3258 Leu Ser Glu Ser Gln Ser Glu Leu Glu Glu LysGln Thr Ser Ala Leu 1000 1005 1010 tct ggt gga gtc cag gtc gag cca cctgca cac agt gac tcc ctg gac 3306 Ser Gly Gly Val Gln Val Glu Pro Pro AlaHis Ser Asp Ser Leu Asp 1015 1020 1025 1030 ccc cag acc aac agc caa cagcag acc aca cag tac atc atc acc acc 3354 Pro Gln Thr Asn Ser Gln Gln GlnThr Thr Gln Tyr Ile Ile Thr Thr 1035 1040 1045 acc acc aac ggg aac ggaagc agc gaa gtg cat atc acc aaa cca 3399 Thr Thr Asn Gly Asn Gly Ser SerGlu Val His Ile Thr Lys Pro 1050 1055 1060 tgacttccac cctggagcttgaatccagca cccacctcat gtctgttctc ataagtctga 3459 aagctctgac acgtagagctcttttgtaag atttattatt cactcaagag ttcggaaacc 3519 acagttttgt ctctcatccatacactgggg tttattttgc caaggtcatc tttatcaaat 3579 tgactcttca aaccctcggtttttgccaca gaacagagat ctttcagggg aaagtagatt 3639 tcgaggtgga gagaatttgccttgctcttg agctggtctt ttaacatact gacgagcctt 3699 acttttcctt tgtggaaatattaagtggca tattgtgttc ataccaaagg tggagacagg 3759 atgtgccaag ttcatggttactggacttct tattccaagc catggcacca aaggagaagg 3819 ggcattttgt gggtgtgcattaggtctgaa ctgctttatc ttgttttagt tttcagtaat 3879 ttaacaaagg gagcctgctgaataacaaaa ttaaaatgat gaaacaaaag tttgacagtg 3939 atattctgaa gcaaaaactgtcatctaaat ttttcttgct gatttttttt aacttcccta 3999 ttttagaaaa ctattgttgggctgttggta gtgctttcca cagatgctgg tcctcagtgg 4059 attaggtcag aagctcatgttctgatagtt cttcattatt tcacaaaggt ggacaacctg 4119 aaagagaaaa ggctgcttgatgtcagcaga atctaaaccc ctacattaaa gctttgcctc 4179 ccattctgtg gttgtggtggtggtaagaag gagatattgg taccaagaaa aatttccaaa 4239 actattgaga gagagagagagaaagtattg aaattttgtt ctgccttgca ggatccattt 4299 atcattcatt ggtaaaggatatattccttg ttcttaccaa gtgtacattt aactcttgct 4359 gacatgttca gtgtattttattacttttaa tgctgtctta aaatgaacat tctttaaagt 4419 tggacaggaa ggtggcatttcttatttatt aacattttta actttaaaca tattgtgact 4479 catctagacc ttttaataagacgatcaact tcacacttag ggaaaaaatt aaaatgtgat 4539 ggccacttct aataattcaggtagttataa gggatctgga agaaatccag tctttatgaa 4599 tatactatta gttgggcattaaaaaatcag tatatatttt aactttttgt gacatgctaa 4659 cacattttca gaataattattgcatagtag aatttattac tccagaacag aaagacctta 4719 cttcatttca aatgaagttaattaatttac atttctgggt aaaaactggt tctataaatt 4779 aagtagagta gcttctttatgataaagaca attttctgaa aagtgaacaa ttctgttaaa 4839 agaactttat tgatgtgtagatttcgcact ttatttctga gactgcgttc atgtagttgt 4899 tccccaatgt ttgagtactaagagaacttg agaaaattac ttcataaaca tatggaaact 4959 gaaaatggac tctctttgtgacaaagatat tcaacagaaa atattgaccc tgcattgcaa 5019 aacacaggtt cgggttccctaagtcccaca gtgtaatgat tacaaatatc ctagtgtccg 5079 gtctagaaag actttctaggagaagactag tggaattttc taaaggttca gttttagctt 5139 ttataactta aatttggccctgttacgttc tttttaattt gaaccataag gtatctcccc 5199 tcccttcagg aataacttattggaaaactg aaaagaatca ctgaatggaa tgttcatttt 5259 atggcagttg ttttaagttttaaaatacac agaggaaaat attgtggaag gacctctttg 5319 ttgctttccc ttctaagttgtcttcttctt cttcttcttc ttcttcttct ttggtcctta 5379 agtgaaataa agactctaaaactaatttgt atattatcag ccagagatgc ggatggcagt 5439 cgagccaaat cgcatggctttcagatcagg tattctgcac attcattcca aggtcataga 5499 tttttaaaag gacctggatttgaagagatg gcaaatgatg agccatcaga aaacttaatt 5559 tggaaaacat gtatgtagccagtgtggata ttgtggcctc tctcaagaca cattgacact 5619 gtagacttca ttcagtccagtgtgagtatt ttggagtagg ttggatgtag attttgtttt 5679 tatcattgat ttgtaccgacagaaatagac atttcatcat gtaaaattcc tgttattctg 5739 gaaaaaccta ttgttttgatcttcttgttt tctgacttgg aagtatcctt tcaaaaaaac 5799 tcttaagata tctaggtctaaaaagcactt catgagatgc taaagctgac ccactggttg 5859 aaaatgttga ccctatcctgttatttaaat gtgaacattt attgtacatt cagtgagtta 5919 tagtgttaat agtcttgtgctatgcagcag gtgtaaaaat taataaatat attttttaat 5979 aaacatgttt gtatgtgtgagtagtcattt c 6010 4 1061 PRT Homo sapiens 4 Met Ser Ala Tyr Ser Val ProSer Thr Phe Ala Gln Ala Ser Leu Pro 1 5 10 15 Val His Asn Gln Val LeuPro Ser Ile Glu Ser Val Asp Gly Ser Asp 20 25 30 Pro Leu Ala Thr Leu GlnThr Pro Leu Gly Arg Leu Glu Ala Lys Glu 35 40 45 Glu Glu Asp Glu Asp GluAsp Glu Asp Thr Glu Glu Asp Glu Glu Glu 50 55 60 Asp Gly Glu Asp Thr AspLeu Asp Asp Trp Glu Pro Asp Pro Pro Arg 65 70 75 80 Pro Phe Asp Pro HisAsp Leu Trp Cys Glu Glu Cys Asn Asn Ala His 85 90 95 Ala Ser Val Cys ProLys His Gly Pro Leu His Pro Ile Pro Asn Arg 100 105 110 Pro Val Leu ThrArg Ala Arg Ala Ser Leu Pro Leu Val Leu Tyr Ile 115 120 125 Asp Arg PheLeu Gly Gly Val Phe Ser Lys Arg Arg Ile Pro Lys Arg 130 135 140 Thr GlnPhe Gly Pro Val Glu Gly Pro Leu Val Arg Gly Ser Glu Leu 145 150 155 160Lys Asp Cys Tyr Ile His Leu Lys Val Ser Leu Asp Lys Gly Asp Arg 165 170175 Lys Glu Arg Asp Leu His Glu Asp Leu Trp Phe Glu Leu Ser Asp Glu 180185 190 Thr Leu Cys Asn Trp Met Met Phe Val Arg Pro Ala Gln Asn His Leu195 200 205 Glu Gln Asn Leu Val Ala Tyr Gln Tyr Gly His His Val Tyr TyrThr 210 215 220 Thr Ile Lys Asn Val Glu Pro Lys Gln Glu Leu Lys Val TrpTyr Ala 225 230 235 240 Ala Ser Tyr Ala Glu Phe Val Asn Gln Lys Ile HisAsp Ile Ser Glu 245 250 255 Glu Glu Arg Lys Val Leu Arg Glu Gln Glu LysAsn Trp Pro Cys Tyr 260 265 270 Glu Cys Asn Arg Arg Phe Ile Ser Ser GluGln Leu Gln Gln His Leu 275 280 285 Asn Ser His Asp Glu Lys Leu Asp ValPhe Ser Arg Thr Arg Gly Arg 290 295 300 Gly Arg Gly Arg Gly Lys Arg ArgPhe Gly Pro Gly Arg Arg Pro Gly 305 310 315 320 Arg Pro Pro Lys Phe IleArg Leu Glu Ile Thr Ser Glu Asn Gly Glu 325 330 335 Lys Ser Asp Asp GlyThr Gln Asp Leu Leu His Phe Pro Thr Lys Glu 340 345 350 Gln Phe Asp GluAla Glu Pro Ala Thr Leu Asn Gly Leu Asp Gln Pro 355 360 365 Glu Gln ThrThr Ile Pro Ile Pro Gln Leu Pro Gln Glu Thr Gln Ser 370 375 380 Ser LeuGlu His Glu Pro Glu Thr His Thr Leu His Leu Gln Pro Gln 385 390 395 400His Glu Glu Ser Val Val Pro Thr Gln Ser Thr Leu Thr Ala Asp Asp 405 410415 Met Arg Arg Ala Lys Arg Ile Arg Leu Glu Leu Gln Asn Ala Ala Leu 420425 430 Gln His Leu Phe Ile Arg Lys Ser Phe Arg Pro Phe Lys Cys Leu Gln435 440 445 Cys Gly Lys Ala Phe Arg Glu Lys Asp Lys Leu Asp Gln His LeuArg 450 455 460 Phe His Gly Arg Glu Gly Asn Cys Pro Leu Thr Cys Asp LeuCys Asn 465 470 475 480 Lys Gly Phe Ile Ser Ser Thr Ser Leu Glu Ser HisMet Lys Leu His 485 490 495 Ser Asp Gln Lys Thr Tyr Ser Cys Ile Phe CysPro Glu Ser Phe Asp 500 505 510 Arg Leu Asp Leu Leu Lys Asp His Val AlaIle His Ile Asn Asp Gly 515 520 525 Tyr Phe Thr Cys Pro Thr Cys Lys LysArg Phe Pro Asp Phe Ile Gln 530 535 540 Val Lys Lys His Val Arg Ser PheHis Ser Glu Lys Ile Tyr Gln Cys 545 550 555 560 Thr Glu Cys Asp Lys AlaPhe Cys Arg Pro Asp Lys Leu Arg Leu His 565 570 575 Met Leu Arg His SerAsp Arg Lys Asp Phe Leu Cys Ser Thr Cys Gly 580 585 590 Lys Gln Phe LysArg Lys Asp Lys Leu Arg Glu His Met Gln Arg Met 595 600 605 His Asn ProGlu Arg Glu Ala Lys Lys Ala Asp Arg Ile Ser Arg Ser 610 615 620 Lys ThrPhe Lys Pro Arg Ile Thr Ser Thr Asp Tyr Asp Ser Phe Thr 625 630 635 640Phe Lys Cys Arg Leu Cys Met Met Gly Phe Arg Arg Arg Gly Met Leu 645 650655 Val Asn His Leu Ser Lys Arg His Pro Asp Met Lys Ile Glu Glu Val 660665 670 Pro Glu Leu Thr Leu Pro Ile Ile Lys Pro Asn Arg Asp Tyr Phe Cys675 680 685 Gln Tyr Cys Asp Lys Val Tyr Lys Ser Ala Ser Lys Arg Lys AlaHis 690 695 700 Ile Leu Lys Asn His Pro Gly Ala Glu Leu Pro Pro Ser IleArg Lys 705 710 715 720 Leu Arg Pro Ala Gly Pro Gly Glu Pro Asp Pro MetLeu Ser Thr His 725 730 735 Thr Gln Leu Thr Gly Thr Ile Ala Thr Pro ProVal Cys Cys Pro His 740 745 750 Cys Ser Lys Gln Tyr Ser Ser Lys Thr LysMet Val Gln His Ile Arg 755 760 765 Lys Lys His Pro Glu Phe Ala Gln LeuSer Asn Thr Ile His Thr Pro 770 775 780 Leu Thr Thr Ala Val Ile Ser AlaThr Pro Ala Val Leu Thr Thr Asp 785 790 795 800 Ser Ala Thr Gly Glu ThrVal Val Thr Thr Asp Leu Leu Thr Gln Ala 805 810 815 Met Thr Glu Leu SerGln Thr Leu Thr Thr Asp Tyr Arg Thr Pro Gln 820 825 830 Gly Asp Tyr GlnArg Ile Gln Tyr Ile Pro Val Ser Gln Ser Ala Ser 835 840 845 Gly Leu GlnGln Pro Gln His Ile Gln Leu Gln Val Val Gln Val Ala 850 855 860 Ser AlaThr Ser Pro His Gln Ser Gln Gln Ser Thr Val Asp Val Gly 865 870 875 880Gln Leu His Asp Pro Gln Pro Tyr Pro Gln His Ala Ile Gln Val Gln 885 890895 His Ile Gln Val Ser Gly Gln Pro Leu Ser Pro Ser Ala Gln Gln Ala 900905 910 Gln Gln Gly Leu Ser Pro Ser His Ile Gln Gly Ser Ser Ser Thr Gln915 920 925 Gly Gln Ala Leu Gln Gln Gln Gln Gln Gln Gln Gln Asn Ser SerVal 930 935 940 Gln His Thr Tyr Leu Pro Ser Ala Trp Asn Ser Phe Arg GlyTyr Ser 945 950 955 960 Ser Glu Ile Gln Met Met Thr Leu Pro Pro Gly GlnPhe Val Ile Thr 965 970 975 Asp Ser Gly Val Ala Thr Pro Val Thr Thr GlyGln Val Lys Ala Val 980 985 990 Thr Ser Gly His Tyr Val Leu Ser Glu SerGln Ser Glu Leu Glu Glu 995 1000 1005 Lys Gln Thr Ser Ala Leu Ser GlyGly Val Gln Val Glu Pro Pro Ala 1010 1015 1020 His Ser Asp Ser Leu AspPro Gln Thr Asn Ser Gln Gln Gln Thr Thr 1025 1030 1035 1040 Gln Tyr IleIle Thr Thr Thr Thr Asn Gly Asn Gly Ser Ser Glu Val 1045 1050 1055 HisIle Thr Lys Pro 1060 5 2208 DNA Homo sapiens CDS (250)...(1761) 5gtcttgagga ccatctctcc cggcagcata ccgtgtggct tcacactgct ctgcctctct 60gaacctcggt ttcttcatct ataaaatggg aataagagta agccacctca atggactgtg 120ggaggcttaa gtaaattgaa gtgccatgca agtagctagc atgcagttgc agctcaatga 180atattatgat ggccgcagat acgatggcta cagctggggc acccatttcg ggtcacaagg 240tagggttca atg ttg aag atg gca gag cca att gca tcc ctg atg atc gtg 291Met Leu Lys Met Ala Glu Pro Ile Ala Ser Leu Met Ile Val 1 5 10 gag tgccgg gcc tgc ctg aga tgc tca cct ctc ttc ctt tac cag aga 339 Glu Cys ArgAla Cys Leu Arg Cys Ser Pro Leu Phe Leu Tyr Gln Arg 15 20 25 30 gag aaagac aga atg acc gag aac atg aag gag tgc ttg gcc cag acc 387 Glu Lys AspArg Met Thr Glu Asn Met Lys Glu Cys Leu Ala Gln Thr 35 40 45 aat gca gccgtg ggg gat atg gtg acg gtg gtg aat ccg agc cag gag 435 Asn Ala Ala ValGly Asp Met Val Thr Val Val Asn Pro Ser Gln Glu 50 55 60 tat ggc cag ccctgc tct agg aga ccg gac tcc tcg gcc atg gaa gtt 483 Tyr Gly Gln Pro CysSer Arg Arg Pro Asp Ser Ser Ala Met Glu Val 65 70 75 gag ccc aag aaa ctgaaa ggg aag cgc gac ctc atc gtg ccc aaa agc 531 Glu Pro Lys Lys Leu LysGly Lys Arg Asp Leu Ile Val Pro Lys Ser 80 85 90 ttc cag caa gtg gac ttctgg ttt tgt gag tcc tgc cag gag tac ttc 579 Phe Gln Gln Val Asp Phe TrpPhe Cys Glu Ser Cys Gln Glu Tyr Phe 95 100 105 110 gtg gat gaa tgc ccaaac cat ggc ccc ccg gtg ttt gtg tct gac aca 627 Val Asp Glu Cys Pro AsnHis Gly Pro Pro Val Phe Val Ser Asp Thr 115 120 125 ccg gtg ccc gtg ggcatc cca gac cgg gcg gcg ctc acc atc cca cag 675 Pro Val Pro Val Gly IlePro Asp Arg Ala Ala Leu Thr Ile Pro Gln 130 135 140 ggc atg gag gtg gtcaag gac act agt gga gag agt gac gtg cga tgt 723 Gly Met Glu Val Val LysAsp Thr Ser Gly Glu Ser Asp Val Arg Cys 145 150 155 gta aac gag gtc atcccc aag ggc cac atc ttc ggc ccc tat gag ggg 771 Val Asn Glu Val Ile ProLys Gly His Ile Phe Gly Pro Tyr Glu Gly 160 165 170 cag atc tcc acc caggac aaa tca gct ggc ttc ttc tcc tgg ctg att 819 Gln Ile Ser Thr Gln AspLys Ser Ala Gly Phe Phe Ser Trp Leu Ile 175 180 185 190 gtg gac aag aacaac cgc tat aag tcc ata gat ggc tca gac gag acc 867 Val Asp Lys Asn AsnArg Tyr Lys Ser Ile Asp Gly Ser Asp Glu Thr 195 200 205 gaa gcc aac tggatg agg tac gtg gtc atc tcc cgg gag gag agg gag 915 Glu Ala Asn Trp MetArg Tyr Val Val Ile Ser Arg Glu Glu Arg Glu 210 215 220 cag aac ctg ctggcg ttc cag cac agt gag cgc atc tac ttc cgg gcg 963 Gln Asn Leu Leu AlaPhe Gln His Ser Glu Arg Ile Tyr Phe Arg Ala 225 230 235 tgc agg gac atccgg cct ggg gag tgg ctg cgg gtc tgg tac agc gag 1011 Cys Arg Asp Ile ArgPro Gly Glu Trp Leu Arg Val Trp Tyr Ser Glu 240 245 250 gac tac atg aagcgc ctg cac agc atg tcc cag gaa acc att cac cgc 1059 Asp Tyr Met Lys ArgLeu His Ser Met Ser Gln Glu Thr Ile His Arg 255 260 265 270 aac ctg gccaga gga gag aag agg ttg cag agg gag aag tct gag cag 1107 Asn Leu Ala ArgGly Glu Lys Arg Leu Gln Arg Glu Lys Ser Glu Gln 275 280 285 gtt ctg gataac cca gaa gac ctg agg ggt ccc att cat ctc tct gtg 1155 Val Leu Asp AsnPro Glu Asp Leu Arg Gly Pro Ile His Leu Ser Val 290 295 300 ctg aga cagggc aaa agt ccc tac aag cgt ggc ttc gat gag ggg gat 1203 Leu Arg Gln GlyLys Ser Pro Tyr Lys Arg Gly Phe Asp Glu Gly Asp 305 310 315 gta cac ccccaa gct aag aag aag aaa att gac ctg att ttc aag gat 1251 Val His Pro GlnAla Lys Lys Lys Lys Ile Asp Leu Ile Phe Lys Asp 320 325 330 gtt ctg gaggcc tca ctg gaa tct gcg aag gtg gaa gcc cac cag ttg 1299 Val Leu Glu AlaSer Leu Glu Ser Ala Lys Val Glu Ala His Gln Leu 335 340 345 350 gcc ctgagc acc tca ctg gtc atc agg aaa gtc ccc aaa tac cag gat 1347 Ala Leu SerThr Ser Leu Val Ile Arg Lys Val Pro Lys Tyr Gln Asp 355 360 365 gac gcctac agt cag tgt gca aca aca atg acc cat ggt gtg cag aat 1395 Asp Ala TyrSer Gln Cys Ala Thr Thr Met Thr His Gly Val Gln Asn 370 375 380 ata ggccag acc cag ggg gag ggg gac tgg aag gtc ccc cag ggg gtc 1443 Ile Gly GlnThr Gln Gly Glu Gly Asp Trp Lys Val Pro Gln Gly Val 385 390 395 tcc aaggag cca ggc caa ttg gag gat gaa gaa gag gag cct tca tca 1491 Ser Lys GluPro Gly Gln Leu Glu Asp Glu Glu Glu Glu Pro Ser Ser 400 405 410 ttc aaggcc gac agt cct gcc gag gcc tcc ctt gca tct gac cct cat 1539 Phe Lys AlaAsp Ser Pro Ala Glu Ala Ser Leu Ala Ser Asp Pro His 415 420 425 430 gaactt ccc acc acc tct ttt tgc cct aac tgt att cgc cta aag aag 1587 Glu LeuPro Thr Thr Ser Phe Cys Pro Asn Cys Ile Arg Leu Lys Lys 435 440 445 aaggtt cgg gag ctc cag gca gaa tta gac atg ctt aag tct ggg aaa 1635 Lys ValArg Glu Leu Gln Ala Glu Leu Asp Met Leu Lys Ser Gly Lys 450 455 460 cttcct gag ccc ccc gta ttg cca cca cag gta ctg gag ctc cca gag 1683 Leu ProGlu Pro Pro Val Leu Pro Pro Gln Val Leu Glu Leu Pro Glu 465 470 475 ttctcg gac cct gca ggt aag ttg gtt tgg atg aga tta ttg tcg gag 1731 Phe SerAsp Pro Ala Gly Lys Leu Val Trp Met Arg Leu Leu Ser Glu 480 485 490 ggcaga gta cgc agt ggg ctg tgt gga ggg tagcctaaag ctctctgtgg 1781 Gly ArgVal Arg Ser Gly Leu Cys Gly Gly 495 500 aaaccacctt ccgggagacc tgaggagtgtaacgtggagg cggctacctc cgtgggtggg 1841 agcccaggtc ctcagtgtct ctggcagacccatcggcagc tctgccaggt gctccatgtg 1901 ttgcccttgt atcctccttg tcaataaaggaagttccgct gcagaagggg tgtgtgctgt 1961 gttcttgacc cgttgccttt ctctggtactggtgtcttac cccaaagccc aatttctaaa 2021 cccagtcttt ctctgtcccc agtctcaagcagggtgtccc actggagaga tctcttggct 2081 tccctaactt agtccaggaa cacagccttgttcttctctt cctgaatctc tgtcctgcca 2141 cacatggtcc cagttcccta gcctggagttctagaaggat ggagagtgag gggatccagg 2201 ccattca 2208 6 504 PRT Homosapiens 6 Met Leu Lys Met Ala Glu Pro Ile Ala Ser Leu Met Ile Val GluCys 1 5 10 15 Arg Ala Cys Leu Arg Cys Ser Pro Leu Phe Leu Tyr Gln ArgGlu Lys 20 25 30 Asp Arg Met Thr Glu Asn Met Lys Glu Cys Leu Ala Gln ThrAsn Ala 35 40 45 Ala Val Gly Asp Met Val Thr Val Val Asn Pro Ser Gln GluTyr Gly 50 55 60 Gln Pro Cys Ser Arg Arg Pro Asp Ser Ser Ala Met Glu ValGlu Pro 65 70 75 80 Lys Lys Leu Lys Gly Lys Arg Asp Leu Ile Val Pro LysSer Phe Gln 85 90 95 Gln Val Asp Phe Trp Phe Cys Glu Ser Cys Gln Glu TyrPhe Val Asp 100 105 110 Glu Cys Pro Asn His Gly Pro Pro Val Phe Val SerAsp Thr Pro Val 115 120 125 Pro Val Gly Ile Pro Asp Arg Ala Ala Leu ThrIle Pro Gln Gly Met 130 135 140 Glu Val Val Lys Asp Thr Ser Gly Glu SerAsp Val Arg Cys Val Asn 145 150 155 160 Glu Val Ile Pro Lys Gly His IlePhe Gly Pro Tyr Glu Gly Gln Ile 165 170 175 Ser Thr Gln Asp Lys Ser AlaGly Phe Phe Ser Trp Leu Ile Val Asp 180 185 190 Lys Asn Asn Arg Tyr LysSer Ile Asp Gly Ser Asp Glu Thr Glu Ala 195 200 205 Asn Trp Met Arg TyrVal Val Ile Ser Arg Glu Glu Arg Glu Gln Asn 210 215 220 Leu Leu Ala PheGln His Ser Glu Arg Ile Tyr Phe Arg Ala Cys Arg 225 230 235 240 Asp IleArg Pro Gly Glu Trp Leu Arg Val Trp Tyr Ser Glu Asp Tyr 245 250 255 MetLys Arg Leu His Ser Met Ser Gln Glu Thr Ile His Arg Asn Leu 260 265 270Ala Arg Gly Glu Lys Arg Leu Gln Arg Glu Lys Ser Glu Gln Val Leu 275 280285 Asp Asn Pro Glu Asp Leu Arg Gly Pro Ile His Leu Ser Val Leu Arg 290295 300 Gln Gly Lys Ser Pro Tyr Lys Arg Gly Phe Asp Glu Gly Asp Val His305 310 315 320 Pro Gln Ala Lys Lys Lys Lys Ile Asp Leu Ile Phe Lys AspVal Leu 325 330 335 Glu Ala Ser Leu Glu Ser Ala Lys Val Glu Ala His GlnLeu Ala Leu 340 345 350 Ser Thr Ser Leu Val Ile Arg Lys Val Pro Lys TyrGln Asp Asp Ala 355 360 365 Tyr Ser Gln Cys Ala Thr Thr Met Thr His GlyVal Gln Asn Ile Gly 370 375 380 Gln Thr Gln Gly Glu Gly Asp Trp Lys ValPro Gln Gly Val Ser Lys 385 390 395 400 Glu Pro Gly Gln Leu Glu Asp GluGlu Glu Glu Pro Ser Ser Phe Lys 405 410 415 Ala Asp Ser Pro Ala Glu AlaSer Leu Ala Ser Asp Pro His Glu Leu 420 425 430 Pro Thr Thr Ser Phe CysPro Asn Cys Ile Arg Leu Lys Lys Lys Val 435 440 445 Arg Glu Leu Gln AlaGlu Leu Asp Met Leu Lys Ser Gly Lys Leu Pro 450 455 460 Glu Pro Pro ValLeu Pro Pro Gln Val Leu Glu Leu Pro Glu Phe Ser 465 470 475 480 Asp ProAla Gly Lys Leu Val Trp Met Arg Leu Leu Ser Glu Gly Arg 485 490 495 ValArg Ser Gly Leu Cys Gly Gly 500 7 1437 DNA Homo sapiens CDS(61)...(1161) 7 cccgcccacc tcccccgtcg gcccggccgt cccccggcgc cggggagctccgggccgccc 60 atg atg ggc tcc gtg ctc ccg gct gag gcc ctg gtg ctc aagacc ggg 108 Met Met Gly Ser Val Leu Pro Ala Glu Ala Leu Val Leu Lys ThrGly 1 5 10 15 ctg aag gcg ccg gga ctg gcg ctg gcc gag gtt atc acc tccgac atc 156 Leu Lys Ala Pro Gly Leu Ala Leu Ala Glu Val Ile Thr Ser AspIle 20 25 30 ctg cac agc ttc ctg tac ggc cgc tgg cgc aac gtg ctc ggg gagcag 204 Leu His Ser Phe Leu Tyr Gly Arg Trp Arg Asn Val Leu Gly Glu Gln35 40 45 ctc ttc gag gac aag agc cac cac gcc agc ccc aag aca gcc ttc acc252 Leu Phe Glu Asp Lys Ser His His Ala Ser Pro Lys Thr Ala Phe Thr 5055 60 gcc gag gtg ctg gcg cag tcc ttc tcc ggc gaa gtg cag aag ctg tcc300 Ala Glu Val Leu Ala Gln Ser Phe Ser Gly Glu Val Gln Lys Leu Ser 6570 75 80 agc ctg gtg ctg cct gcg gag gtg atc atc gct cag agc tcc atc cct348 Ser Leu Val Leu Pro Ala Glu Val Ile Ile Ala Gln Ser Ser Ile Pro 8590 95 ggc gag ggc ctc ggc atc ttc tcc aag acg tgg atc aag gcg gga acc396 Gly Glu Gly Leu Gly Ile Phe Ser Lys Thr Trp Ile Lys Ala Gly Thr 100105 110 gag atg ggc ccc ttc acc ggc cgc gtg atc gcc ccg gag cac gtg gac444 Glu Met Gly Pro Phe Thr Gly Arg Val Ile Ala Pro Glu His Val Asp 115120 125 atc tgc aag aac aac aac ctc atg tgg gag gtg ttc aat gag gat ggc492 Ile Cys Lys Asn Asn Asn Leu Met Trp Glu Val Phe Asn Glu Asp Gly 130135 140 acg gtg cgc tac ttc atc gat gcc agc cag gag gac cac cgg agc tgg540 Thr Val Arg Tyr Phe Ile Asp Ala Ser Gln Glu Asp His Arg Ser Trp 145150 155 160 atg acc tac atc aag tgt gca cgt aac gaa cag gag cag aac ctggag 588 Met Thr Tyr Ile Lys Cys Ala Arg Asn Glu Gln Glu Gln Asn Leu Glu165 170 175 gtg gtc cag atc ggc acc agc atc ttc tac aag gcc att gag atgatc 636 Val Val Gln Ile Gly Thr Ser Ile Phe Tyr Lys Ala Ile Glu Met Ile180 185 190 cca cct gac cag gaa ctg ctg gtg tgg tac gga aac tca cac aacacc 684 Pro Pro Asp Gln Glu Leu Leu Val Trp Tyr Gly Asn Ser His Asn Thr195 200 205 ttc ctg ggg atc cca ggt gtg ccc ggg cta gag gag gac cag aaaaag 732 Phe Leu Gly Ile Pro Gly Val Pro Gly Leu Glu Glu Asp Gln Lys Lys210 215 220 aac aag cat gag gac ttc cac ccg gcg gac tcg gcg gct ggc cccgcg 780 Asn Lys His Glu Asp Phe His Pro Ala Asp Ser Ala Ala Gly Pro Ala225 230 235 240 ggc cgc atg cga tgc gtc atc tgc cac cgc ggc ttc aac tcgcgc agc 828 Gly Arg Met Arg Cys Val Ile Cys His Arg Gly Phe Asn Ser ArgSer 245 250 255 aac ctg cgc tcg cac atg cgc atc cac acg ctg gac aag cccttc gtg 876 Asn Leu Arg Ser His Met Arg Ile His Thr Leu Asp Lys Pro PheVal 260 265 270 tgc cgc ttc tgc aac cgc cgc ttc agc cag tcg tcc acg ctgcgc aac 924 Cys Arg Phe Cys Asn Arg Arg Phe Ser Gln Ser Ser Thr Leu ArgAsn 275 280 285 cac gtg cgc ctg cac acg ggc gag cgc ccc tac aag tgc caggtg tgc 972 His Val Arg Leu His Thr Gly Glu Arg Pro Tyr Lys Cys Gln ValCys 290 295 300 cag agc gcc tac tcg cag ctg gcc ggc ctg cgc gcc cac cagaag agc 1020 Gln Ser Ala Tyr Ser Gln Leu Ala Gly Leu Arg Ala His Gln LysSer 305 310 315 320 gcg cgg cac cgg ccg ccc agc acc gcg ctg cag gca cactcg ccc gcg 1068 Ala Arg His Arg Pro Pro Ser Thr Ala Leu Gln Ala His SerPro Ala 325 330 335 ctg ccc gcc ccg cac gcg cac gcg ccc gcg ctc gcc gccgcc gcc gcc 1116 Leu Pro Ala Pro His Ala His Ala Pro Ala Leu Ala Ala AlaAla Ala 340 345 350 gcc gcc gcc gcc gcc gcc gcg cac cac ctg ccg gcc atggtg ctg 1161 Ala Ala Ala Ala Ala Ala Ala His His Leu Pro Ala Met Val Leu355 360 365 tgagcgcgcc cgcgcccccg ccgggccccg cgcgctcctg ggtccccggcaccccggccc 1221 cgcagcgcga ctcgccctcc agccccaacc cccggcccgg cgccgccgcggagccccgcg 1281 cgctggggtt gcgccccgga ggcggatctc aggcaccccc gccttggcccgtgtcgcaga 1341 tgaggacact gagggcggcg tccctcaccc aggccacgca gctggtgcggctgttcggcc 1401 gcctcctctg ggagggggtc cccctgcctg gcctcg 1437 8 367 PRTHomo sapiens 8 Met Met Gly Ser Val Leu Pro Ala Glu Ala Leu Val Leu LysThr Gly 1 5 10 15 Leu Lys Ala Pro Gly Leu Ala Leu Ala Glu Val Ile ThrSer Asp Ile 20 25 30 Leu His Ser Phe Leu Tyr Gly Arg Trp Arg Asn Val LeuGly Glu Gln 35 40 45 Leu Phe Glu Asp Lys Ser His His Ala Ser Pro Lys ThrAla Phe Thr 50 55 60 Ala Glu Val Leu Ala Gln Ser Phe Ser Gly Glu Val GlnLys Leu Ser 65 70 75 80 Ser Leu Val Leu Pro Ala Glu Val Ile Ile Ala GlnSer Ser Ile Pro 85 90 95 Gly Glu Gly Leu Gly Ile Phe Ser Lys Thr Trp IleLys Ala Gly Thr 100 105 110 Glu Met Gly Pro Phe Thr Gly Arg Val Ile AlaPro Glu His Val Asp 115 120 125 Ile Cys Lys Asn Asn Asn Leu Met Trp GluVal Phe Asn Glu Asp Gly 130 135 140 Thr Val Arg Tyr Phe Ile Asp Ala SerGln Glu Asp His Arg Ser Trp 145 150 155 160 Met Thr Tyr Ile Lys Cys AlaArg Asn Glu Gln Glu Gln Asn Leu Glu 165 170 175 Val Val Gln Ile Gly ThrSer Ile Phe Tyr Lys Ala Ile Glu Met Ile 180 185 190 Pro Pro Asp Gln GluLeu Leu Val Trp Tyr Gly Asn Ser His Asn Thr 195 200 205 Phe Leu Gly IlePro Gly Val Pro Gly Leu Glu Glu Asp Gln Lys Lys 210 215 220 Asn Lys HisGlu Asp Phe His Pro Ala Asp Ser Ala Ala Gly Pro Ala 225 230 235 240 GlyArg Met Arg Cys Val Ile Cys His Arg Gly Phe Asn Ser Arg Ser 245 250 255Asn Leu Arg Ser His Met Arg Ile His Thr Leu Asp Lys Pro Phe Val 260 265270 Cys Arg Phe Cys Asn Arg Arg Phe Ser Gln Ser Ser Thr Leu Arg Asn 275280 285 His Val Arg Leu His Thr Gly Glu Arg Pro Tyr Lys Cys Gln Val Cys290 295 300 Gln Ser Ala Tyr Ser Gln Leu Ala Gly Leu Arg Ala His Gln LysSer 305 310 315 320 Ala Arg His Arg Pro Pro Ser Thr Ala Leu Gln Ala HisSer Pro Ala 325 330 335 Leu Pro Ala Pro His Ala His Ala Pro Ala Leu AlaAla Ala Ala Ala 340 345 350 Ala Ala Ala Ala Ala Ala Ala His His Leu ProAla Met Val Leu 355 360 365 9 3234 DNA Homo sapiens CDS (262)...(2412) 9ccatgtgacc ctctcgggtg ggactctgca gctgcttcgc agcgcaactc tctcaccaaa 60ctccgcgccc ttgcgctagc ggtgccaaaa ggctcccgcc ccgattgaaa aggcgcagtg 120catgcccgcc cgcgtcactc cgcgggcgga ggacgcacgt cggggcgcgg ctctctggct 180agcgcgcagc tccagctctg tcactcgcgc ccttccaagg acctggagca cccgagcgcc 240tgcctggtgg cggcggcaac a atg cac gga gcc gcc aga gcg cca gcc acc 291 MetHis Gly Ala Ala Arg Ala Pro Ala Thr 1 5 10 agc gtg agt gcc gac tgc tgcatc ccg gcc ggc ttg cgc ctc gga ccg 339 Ser Val Ser Ala Asp Cys Cys IlePro Ala Gly Leu Arg Leu Gly Pro 15 20 25 gtg cct ggt acc ttc aag ctg ggcaag tac ctg tca gac cgc agg gag 387 Val Pro Gly Thr Phe Lys Leu Gly LysTyr Leu Ser Asp Arg Arg Glu 30 35 40 ccc ggg cct aag aaa aag gta ttg accatt cag acc tct gcc cac cag 435 Pro Gly Pro Lys Lys Lys Val Leu Thr IleGln Thr Ser Ala His Gln 45 50 55 gtg cgc atg gtg aga ggg gag ctg gtg gacgag tcg ggg ggc tcc cct 483 Val Arg Met Val Arg Gly Glu Leu Val Asp GluSer Gly Gly Ser Pro 60 65 70 ctg gag tgg ata ggg tta atc cgg gca gcc agaaac tcc cag gaa cag 531 Leu Glu Trp Ile Gly Leu Ile Arg Ala Ala Arg AsnSer Gln Glu Gln 75 80 85 90 act ctg gaa gct att gca gac tta ccc gga ggacag atc ttc tac cga 579 Thr Leu Glu Ala Ile Ala Asp Leu Pro Gly Gly GlnIle Phe Tyr Arg 95 100 105 gca ttg cga gac gtc cag cca ggg gag gag ctgaca gtg tgg tat tct 627 Ala Leu Arg Asp Val Gln Pro Gly Glu Glu Leu ThrVal Trp Tyr Ser 110 115 120 aac tcc ttg gct cag tgg ttc gac atc ccc accaca gcg act ccg act 675 Asn Ser Leu Ala Gln Trp Phe Asp Ile Pro Thr ThrAla Thr Pro Thr 125 130 135 cac gac gag aaa ggg gag gag cgc tac atc tgctgg tac tgc tgg agg 723 His Asp Glu Lys Gly Glu Glu Arg Tyr Ile Cys TrpTyr Cys Trp Arg 140 145 150 acg ttt aga tac ccc aac agc ctt aag gca cacctg cgt ttc cac tgc 771 Thr Phe Arg Tyr Pro Asn Ser Leu Lys Ala His LeuArg Phe His Cys 155 160 165 170 gtg ttc agc ggc ggt gga ggc ggc gcc ttcctg cac cac gaa cac gcg 819 Val Phe Ser Gly Gly Gly Gly Gly Ala Phe LeuHis His Glu His Ala 175 180 185 gct cgc caa ggc gcc gtc cca gcg gct gatggc ctc ggt ctc tcc cca 867 Ala Arg Gln Gly Ala Val Pro Ala Ala Asp GlyLeu Gly Leu Ser Pro 190 195 200 aaa ccc ccg gcg ccc gat ttc gcc gcg ccttcc cag gca gga act ttg 915 Lys Pro Pro Ala Pro Asp Phe Ala Ala Pro SerGln Ala Gly Thr Leu 205 210 215 cga ccc cac ccc ctg ggc ccg cca cca gttcag gcc tgc ggt gcg cgg 963 Arg Pro His Pro Leu Gly Pro Pro Pro Val GlnAla Cys Gly Ala Arg 220 225 230 gag ggc atc aag cgc gag gcc tct tcc gcgccc tcg gcc acc tcg ccg 1011 Glu Gly Ile Lys Arg Glu Ala Ser Ser Ala ProSer Ala Thr Ser Pro 235 240 245 250 acc cca ggc aag tgg ggg cag ccc aagaag ggc aag gag cag ctg gac 1059 Thr Pro Gly Lys Trp Gly Gln Pro Lys LysGly Lys Glu Gln Leu Asp 255 260 265 cgt gcc ctg gac atg agc gga gcc gcccga gga caa ggg cac ttc ctc 1107 Arg Ala Leu Asp Met Ser Gly Ala Ala ArgGly Gln Gly His Phe Leu 270 275 280 ggc atc gtg ggc ggc tcc tcg gcg ggggtc ggc agc ctg gct ttc tac 1155 Gly Ile Val Gly Gly Ser Ser Ala Gly ValGly Ser Leu Ala Phe Tyr 285 290 295 ccc ggc gtg cgc tca gct ttc aag cccgcc ggc cta gcg agg gcg gcg 1203 Pro Gly Val Arg Ser Ala Phe Lys Pro AlaGly Leu Ala Arg Ala Ala 300 305 310 gcg gcc gct cac ggc gac ccc tac cgggag gag agc agc agc aag caa 1251 Ala Ala Ala His Gly Asp Pro Tyr Arg GluGlu Ser Ser Ser Lys Gln 315 320 325 330 gga gcc ggc ctc gct ttg ggc aggctg ctg ggc ggg ggc cgg gcg tgc 1299 Gly Ala Gly Leu Ala Leu Gly Arg LeuLeu Gly Gly Gly Arg Ala Cys 335 340 345 ggg cgc ccc ggg agc ggg gag aactcg gcg gcg ggc ggc gcg ggt cac 1347 Gly Arg Pro Gly Ser Gly Glu Asn SerAla Ala Gly Gly Ala Gly His 350 355 360 cac cat cac cac cac gcg cac caccac cac cat ccc aag tgc ctg ctc 1395 His His His His His Ala His His HisHis His Pro Lys Cys Leu Leu 365 370 375 gct ggg gac ccg ccg ccg ccg ccgccg cct ggc ctg ccc tgc tct ggg 1443 Ala Gly Asp Pro Pro Pro Pro Pro ProPro Gly Leu Pro Cys Ser Gly 380 385 390 gcc ctg cgc ggc ttc cct ctg ctctcc gtc ccc ccg gaa gag gcg tcc 1491 Ala Leu Arg Gly Phe Pro Leu Leu SerVal Pro Pro Glu Glu Ala Ser 395 400 405 410 gcc ttc aag cac gtg gag cgcgcc ccg ccc gca gcc gcc gcg ctg cca 1539 Ala Phe Lys His Val Glu Arg AlaPro Pro Ala Ala Ala Ala Leu Pro 415 420 425 gga gcg cgt tat gcg cag ctgccc cct gcg ccg ggg ttg ccc ctc gag 1587 Gly Ala Arg Tyr Ala Gln Leu ProPro Ala Pro Gly Leu Pro Leu Glu 430 435 440 cgc tgc gcg ctg ccg ccc ctcgac ccg ggc ggt ctc aaa gcc tat ccg 1635 Arg Cys Ala Leu Pro Pro Leu AspPro Gly Gly Leu Lys Ala Tyr Pro 445 450 455 ggt ggt gag tgc agc cac ctgccc gcc gtc atg ccg gcc ttt aca gtc 1683 Gly Gly Glu Cys Ser His Leu ProAla Val Met Pro Ala Phe Thr Val 460 465 470 tac aac ggg gag ctg ctc tacggc tca ccg gcc acc acc gct tat tac 1731 Tyr Asn Gly Glu Leu Leu Tyr GlySer Pro Ala Thr Thr Ala Tyr Tyr 475 480 485 490 ccg ctc aaa ttg cac ttcggc ggg ctg ctg aag tat ccg gag tcc atc 1779 Pro Leu Lys Leu His Phe GlyGly Leu Leu Lys Tyr Pro Glu Ser Ile 495 500 505 tcc tac ttc agc ggg cctgca gcg gcc gcc cta agc ccc gcc gag ctg 1827 Ser Tyr Phe Ser Gly Pro AlaAla Ala Ala Leu Ser Pro Ala Glu Leu 510 515 520 ggg tcg ctg gcc agc atcgac cga gag atc gcc atg cac aat cag cag 1875 Gly Ser Leu Ala Ser Ile AspArg Glu Ile Ala Met His Asn Gln Gln 525 530 535 ctg tcc gag atg gct gccggg aag ggt cgc gga cgc ctg gac tcg ggg 1923 Leu Ser Glu Met Ala Ala GlyLys Gly Arg Gly Arg Leu Asp Ser Gly 540 545 550 acg ttg cca ccg gcc gtcgcg gcg gcg gga ggc acc ggg ggc ggc ggc 1971 Thr Leu Pro Pro Ala Val AlaAla Ala Gly Gly Thr Gly Gly Gly Gly 555 560 565 570 agc gga ggc agc ggcgca ggt aag ccc aag acc ggc cac ctg tgc ctc 2019 Ser Gly Gly Ser Gly AlaGly Lys Pro Lys Thr Gly His Leu Cys Leu 575 580 585 tac tgt ggc aag ctgtac tcg cgc aag tat ggg ctc aag atc cac atg 2067 Tyr Cys Gly Lys Leu TyrSer Arg Lys Tyr Gly Leu Lys Ile His Met 590 595 600 cgg acg cac acg ggctac aag cca ctc aag tgc aaa gtc tgt ctg cgg 2115 Arg Thr His Thr Gly TyrLys Pro Leu Lys Cys Lys Val Cys Leu Arg 605 610 615 ccc ttc ggc gac cccagc aat ctc aac aag cac atc cgg ctg cac gcc 2163 Pro Phe Gly Asp Pro SerAsn Leu Asn Lys His Ile Arg Leu His Ala 620 625 630 gag ggc aat acg ccctac cgc tgc gag ttc tgc ggc aag gta ctt gtg 2211 Glu Gly Asn Thr Pro TyrArg Cys Glu Phe Cys Gly Lys Val Leu Val 635 640 645 650 cgc cgc cgg gacctg gag cga cat gtc aag tcc cgc cac cct ggc cag 2259 Arg Arg Arg Asp LeuGlu Arg His Val Lys Ser Arg His Pro Gly Gln 655 660 665 agt ctg ctc gccaaa gcg ggc gac ggc ccg ggt gcc gag ccc ggc tat 2307 Ser Leu Leu Ala LysAla Gly Asp Gly Pro Gly Ala Glu Pro Gly Tyr 670 675 680 ccc ccg gag cctggg gat ccc aag agc gac gac agt gac gtg gac gtc 2355 Pro Pro Glu Pro GlyAsp Pro Lys Ser Asp Asp Ser Asp Val Asp Val 685 690 695 tgc ttc aca gacgac cag agc gac ccc gag gtt ggg ggc ggc ggg gag 2403 Cys Phe Thr Asp AspGln Ser Asp Pro Glu Val Gly Gly Gly Gly Glu 700 705 710 cgc gac ttgtaacgagtct tcccgggaag gggcggggtg aggacagaga 2452 Arg Asp Leu 715ggagtcgagg gtttattctc gcagtagagg aactcctggt ggtgggaaga gggacccaat 2512ggacaaaacc gtttttgttt ttgagagggc gccagatttg aaacagtgag aggtcccaca 2572tctggtgctg aaactcagag caacagttca gaggtggcgt aaatctggcc acctggagag 2632ctcgagtgcc accagtacct ccgcaccccg ggcctctgga cttcttggat gagctcaccc 2692tgaaccgccc aggcggtctg ctcttggtgt tcagaatcac atcaatgcga acgtcacagc 2752gccttcgagg gcgcagattt taactgccac gtatttttaa gttgtacttt tctgtggagg 2812aaattgtgcc ttttgaaacg acgttttgtg tgtgtatttc acgttagcat ttcattgcat 2872aggcaaaaca ctagtcacaa ttgggtagat gtgacatcca tatacttgtt tacattttat 2932ctgttctcat gtcaaagact actccttgcc ccattgaata tatagtggta gcaggtgtac 2992aaattggtca agttgcaatt atttatgaga gaataatgat aaatgtaaaa tatctaaagc 3052atgaatctaa gagcacgcaa tatataattt taaagaaaat attctatttg gtagaataca 3112aatgtggtgt gtgttgtttt ataatgactg ctgtacagtg ggtatagtat tttggttttg 3172gttccagatt gtgcaatctt taagaaaaat aaagatacaa acgagagttt tgttcactta 3232gt 3234 10 717 PRT Homo sapiens 10 Met His Gly Ala Ala Arg Ala Pro AlaThr Ser Val Ser Ala Asp Cys 1 5 10 15 Cys Ile Pro Ala Gly Leu Arg LeuGly Pro Val Pro Gly Thr Phe Lys 20 25 30 Leu Gly Lys Tyr Leu Ser Asp ArgArg Glu Pro Gly Pro Lys Lys Lys 35 40 45 Val Leu Thr Ile Gln Thr Ser AlaHis Gln Val Arg Met Val Arg Gly 50 55 60 Glu Leu Val Asp Glu Ser Gly GlySer Pro Leu Glu Trp Ile Gly Leu 65 70 75 80 Ile Arg Ala Ala Arg Asn SerGln Glu Gln Thr Leu Glu Ala Ile Ala 85 90 95 Asp Leu Pro Gly Gly Gln IlePhe Tyr Arg Ala Leu Arg Asp Val Gln 100 105 110 Pro Gly Glu Glu Leu ThrVal Trp Tyr Ser Asn Ser Leu Ala Gln Trp 115 120 125 Phe Asp Ile Pro ThrThr Ala Thr Pro Thr His Asp Glu Lys Gly Glu 130 135 140 Glu Arg Tyr IleCys Trp Tyr Cys Trp Arg Thr Phe Arg Tyr Pro Asn 145 150 155 160 Ser LeuLys Ala His Leu Arg Phe His Cys Val Phe Ser Gly Gly Gly 165 170 175 GlyGly Ala Phe Leu His His Glu His Ala Ala Arg Gln Gly Ala Val 180 185 190Pro Ala Ala Asp Gly Leu Gly Leu Ser Pro Lys Pro Pro Ala Pro Asp 195 200205 Phe Ala Ala Pro Ser Gln Ala Gly Thr Leu Arg Pro His Pro Leu Gly 210215 220 Pro Pro Pro Val Gln Ala Cys Gly Ala Arg Glu Gly Ile Lys Arg Glu225 230 235 240 Ala Ser Ser Ala Pro Ser Ala Thr Ser Pro Thr Pro Gly LysTrp Gly 245 250 255 Gln Pro Lys Lys Gly Lys Glu Gln Leu Asp Arg Ala LeuAsp Met Ser 260 265 270 Gly Ala Ala Arg Gly Gln Gly His Phe Leu Gly IleVal Gly Gly Ser 275 280 285 Ser Ala Gly Val Gly Ser Leu Ala Phe Tyr ProGly Val Arg Ser Ala 290 295 300 Phe Lys Pro Ala Gly Leu Ala Arg Ala AlaAla Ala Ala His Gly Asp 305 310 315 320 Pro Tyr Arg Glu Glu Ser Ser SerLys Gln Gly Ala Gly Leu Ala Leu 325 330 335 Gly Arg Leu Leu Gly Gly GlyArg Ala Cys Gly Arg Pro Gly Ser Gly 340 345 350 Glu Asn Ser Ala Ala GlyGly Ala Gly His His His His His His Ala 355 360 365 His His His His HisPro Lys Cys Leu Leu Ala Gly Asp Pro Pro Pro 370 375 380 Pro Pro Pro ProGly Leu Pro Cys Ser Gly Ala Leu Arg Gly Phe Pro 385 390 395 400 Leu LeuSer Val Pro Pro Glu Glu Ala Ser Ala Phe Lys His Val Glu 405 410 415 ArgAla Pro Pro Ala Ala Ala Ala Leu Pro Gly Ala Arg Tyr Ala Gln 420 425 430Leu Pro Pro Ala Pro Gly Leu Pro Leu Glu Arg Cys Ala Leu Pro Pro 435 440445 Leu Asp Pro Gly Gly Leu Lys Ala Tyr Pro Gly Gly Glu Cys Ser His 450455 460 Leu Pro Ala Val Met Pro Ala Phe Thr Val Tyr Asn Gly Glu Leu Leu465 470 475 480 Tyr Gly Ser Pro Ala Thr Thr Ala Tyr Tyr Pro Leu Lys LeuHis Phe 485 490 495 Gly Gly Leu Leu Lys Tyr Pro Glu Ser Ile Ser Tyr PheSer Gly Pro 500 505 510 Ala Ala Ala Ala Leu Ser Pro Ala Glu Leu Gly SerLeu Ala Ser Ile 515 520 525 Asp Arg Glu Ile Ala Met His Asn Gln Gln LeuSer Glu Met Ala Ala 530 535 540 Gly Lys Gly Arg Gly Arg Leu Asp Ser GlyThr Leu Pro Pro Ala Val 545 550 555 560 Ala Ala Ala Gly Gly Thr Gly GlyGly Gly Ser Gly Gly Ser Gly Ala 565 570 575 Gly Lys Pro Lys Thr Gly HisLeu Cys Leu Tyr Cys Gly Lys Leu Tyr 580 585 590 Ser Arg Lys Tyr Gly LeuLys Ile His Met Arg Thr His Thr Gly Tyr 595 600 605 Lys Pro Leu Lys CysLys Val Cys Leu Arg Pro Phe Gly Asp Pro Ser 610 615 620 Asn Leu Asn LysHis Ile Arg Leu His Ala Glu Gly Asn Thr Pro Tyr 625 630 635 640 Arg CysGlu Phe Cys Gly Lys Val Leu Val Arg Arg Arg Asp Leu Glu 645 650 655 ArgHis Val Lys Ser Arg His Pro Gly Gln Ser Leu Leu Ala Lys Ala 660 665 670Gly Asp Gly Pro Gly Ala Glu Pro Gly Tyr Pro Pro Glu Pro Gly Asp 675 680685 Pro Lys Ser Asp Asp Ser Asp Val Asp Val Cys Phe Thr Asp Asp Gln 690695 700 Ser Asp Pro Glu Val Gly Gly Gly Gly Glu Arg Asp Leu 705 710 71511 2210 DNA Homo sapiens CDS (203)...(1915) 11 aattccctac cctcgacctgtcgatgcccc gcggccccgc ccgccctctt aagcctggct 60 cagccctcag ggcccgcccgaagtctaccg agcccgagtg gcctaccgag cccgagtggc 120 cccgcagcgt ccaggaggcgcccgctccgc ggtggcgctc ttggaggtgg tgtcggagag 180 ccgccgagcg tgcggtcccg ggatg gct cta ccc cgg cca agt gag gcc gtg 232 Met Ala Leu Pro Arg Pro SerGlu Ala Val 1 5 10 cct cag gac aag gtg tgc tac ccg ccg gag agc agc ccgcag aac ctg 280 Pro Gln Asp Lys Val Cys Tyr Pro Pro Glu Ser Ser Pro GlnAsn Leu 15 20 25 gcc gcg tac tac acg cct ttc ccg tcc tat gga cac tac agaaac agc 328 Ala Ala Tyr Tyr Thr Pro Phe Pro Ser Tyr Gly His Tyr Arg AsnSer 30 35 40 ctg gcc acc gtg gag gaa gac ttc caa cct ttc cgg cag ctg gaggcc 376 Leu Ala Thr Val Glu Glu Asp Phe Gln Pro Phe Arg Gln Leu Glu Ala45 50 55 gca gcg tct gct gcc ccc gcc atg ccc ccc ttc ccc ttc cgg atg gcg424 Ala Ala Ser Ala Ala Pro Ala Met Pro Pro Phe Pro Phe Arg Met Ala 6065 70 cct ccc ttg ctg agc ccg ggt ctg ggc cta cag agg gag cct ctc tac472 Pro Pro Leu Leu Ser Pro Gly Leu Gly Leu Gln Arg Glu Pro Leu Tyr 7580 85 90 gat ctg ccc tgg tac agc aag ctg cca ccg tgg tac cca att ccc cac520 Asp Leu Pro Trp Tyr Ser Lys Leu Pro Pro Trp Tyr Pro Ile Pro His 95100 105 gtc ccc agg gaa gtg ccg ccc ttc ctg agc agc agc cac gag tac gcg568 Val Pro Arg Glu Val Pro Pro Phe Leu Ser Ser Ser His Glu Tyr Ala 110115 120 ggt gcc agc agt gaa gat ctg ggc cac caa atc att ggt ggc gac aac616 Gly Ala Ser Ser Glu Asp Leu Gly His Gln Ile Ile Gly Gly Asp Asn 125130 135 gag agt ggc ccg tgt tgt gga cct gac act tta att cca ccg ccc cct664 Glu Ser Gly Pro Cys Cys Gly Pro Asp Thr Leu Ile Pro Pro Pro Pro 140145 150 gcg gat gct tct ctg tta cct gag ggg ctg agg acc tcc cag tta tta712 Ala Asp Ala Ser Leu Leu Pro Glu Gly Leu Arg Thr Ser Gln Leu Leu 155160 165 170 cct tgc tca ccc agc aag cag tca gag gat ggt ccc aaa ccc tccaac 760 Pro Cys Ser Pro Ser Lys Gln Ser Glu Asp Gly Pro Lys Pro Ser Asn175 180 185 caa gaa ggg aag tcc cct gct cgg ttc cag ttc acg gag gag gacctg 808 Gln Glu Gly Lys Ser Pro Ala Arg Phe Gln Phe Thr Glu Glu Asp Leu190 195 200 cac ttc gtt ctg tac ggg gtc act ccc agc ctg gag cac cca gccagc 856 His Phe Val Leu Tyr Gly Val Thr Pro Ser Leu Glu His Pro Ala Ser205 210 215 ctg cac cat gcg att tca ggc ctc ctg gtc ccc cca gac agc tctgga 904 Leu His His Ala Ile Ser Gly Leu Leu Val Pro Pro Asp Ser Ser Gly220 225 230 tct gat tct ctt cct caa act ctg gat aaa gac tcc ctt caa cttcca 952 Ser Asp Ser Leu Pro Gln Thr Leu Asp Lys Asp Ser Leu Gln Leu Pro235 240 245 250 gaa ggt cta tgc ctc atg cag acg gtg ttt ggt gaa gtc ccacat ttt 1000 Glu Gly Leu Cys Leu Met Gln Thr Val Phe Gly Glu Val Pro HisPhe 255 260 265 ggt gtg ttc tgc agt agt ttt atc gcc aaa gga gtc agg tttggg ccc 1048 Gly Val Phe Cys Ser Ser Phe Ile Ala Lys Gly Val Arg Phe GlyPro 270 275 280 ttt caa ggt aaa gtg gtc aat gcc agt gaa gtg aag acc tacgga gac 1096 Phe Gln Gly Lys Val Val Asn Ala Ser Glu Val Lys Thr Tyr GlyAsp 285 290 295 aat tct gtg atg tgg gag atc ttt gaa gat ggt cat ttg agccac ttt 1144 Asn Ser Val Met Trp Glu Ile Phe Glu Asp Gly His Leu Ser HisPhe 300 305 310 ata gat gga aaa gga ggt acg ggg aac tgg atg tcc tat gtcaac tgt 1192 Ile Asp Gly Lys Gly Gly Thr Gly Asn Trp Met Ser Tyr Val AsnCys 315 320 325 330 gcc cgc ttc ccc aag gag cag aac cta gtt gct gtg cagtgt caa ggg 1240 Ala Arg Phe Pro Lys Glu Gln Asn Leu Val Ala Val Gln CysGln Gly 335 340 345 cat ata ttt tat gag agc tgc aaa gag atc cat cag aaccaa gag ctc 1288 His Ile Phe Tyr Glu Ser Cys Lys Glu Ile His Gln Asn GlnGlu Leu 350 355 360 ctt gtg tgg tat gga gac tgc tat gag aaa ttt ctg gatatt cct gtg 1336 Leu Val Trp Tyr Gly Asp Cys Tyr Glu Lys Phe Leu Asp IlePro Val 365 370 375 agc ctt cag gtc aca gag ccg ggg aag cag cca tct gggccc tct gaa 1384 Ser Leu Gln Val Thr Glu Pro Gly Lys Gln Pro Ser Gly ProSer Glu 380 385 390 gag tct gca gaa ggc tac aga tgt gaa aga tgt ggg aaggta ttt acc 1432 Glu Ser Ala Glu Gly Tyr Arg Cys Glu Arg Cys Gly Lys ValPhe Thr 395 400 405 410 tac aaa tat tac aga gat aag cac ctc aag tac accccc tgt gtg gac 1480 Tyr Lys Tyr Tyr Arg Asp Lys His Leu Lys Tyr Thr ProCys Val Asp 415 420 425 aag ggc gat agg aaa ttt ccc tgt tct ctc tgc aaacga tcc ttt gag 1528 Lys Gly Asp Arg Lys Phe Pro Cys Ser Leu Cys Lys ArgSer Phe Glu 430 435 440 aag cgg gac cgg ctt cgg atc cac att ctt cat gttcat gag aag cac 1576 Lys Arg Asp Arg Leu Arg Ile His Ile Leu His Val HisGlu Lys His 445 450 455 cgg cct cac aag tgt tct aca tgt ggg aaa tgt ttctct cag tct tcc 1624 Arg Pro His Lys Cys Ser Thr Cys Gly Lys Cys Phe SerGln Ser Ser 460 465 470 agc cta aac aaa cac atg cga gtc cac tct gga gacaga cca tac cag 1672 Ser Leu Asn Lys His Met Arg Val His Ser Gly Asp ArgPro Tyr Gln 475 480 485 490 tgt gtg tat tgt act aag agg ttc aca gcc tccagc ata ctc cgc aca 1720 Cys Val Tyr Cys Thr Lys Arg Phe Thr Ala Ser SerIle Leu Arg Thr 495 500 505 cac atc agg cag cac tcc ggg gag aag ccc ttcaaa tgc aag tac tgt 1768 His Ile Arg Gln His Ser Gly Glu Lys Pro Phe LysCys Lys Tyr Cys 510 515 520 ggt aaa tct ttt gca tcc cat gct gcc cat gacagc cat gtc cgg cgt 1816 Gly Lys Ser Phe Ala Ser His Ala Ala His Asp SerHis Val Arg Arg 525 530 535 tca cac aag gag gat gat ggc tgc tca tgc agcatc tgt ggg aaa atc 1864 Ser His Lys Glu Asp Asp Gly Cys Ser Cys Ser IleCys Gly Lys Ile 540 545 550 ttc tca gat caa gaa aca ttc tac tcc cac atgaag ttt cat gaa gac 1912 Phe Ser Asp Gln Glu Thr Phe Tyr Ser His Met LysPhe His Glu Asp 555 560 565 570 tac tagccctgcc aggcacaatg actcacgcctgtaatcccag cactttggga 1965 Tyr ggcagaggtg ggtggatcac tcaagtccaggagttcgaga ccagcctggg caacatggtg 2025 aaatcctgtc tctaccaaaa aaatacaaaaatcagctggg ggtggtggca catgcctgtg 2085 gttccagcca ctcaggaggt cgaggtggcgggatggtttg agcacaggag acggaggttg 2145 ctgtgagctg agatcgcccc actgcttttcaacctgggtg acagaaccag accctgtctc 2205 aaaac 2210 12 571 PRT Homo sapiens12 Met Ala Leu Pro Arg Pro Ser Glu Ala Val Pro Gln Asp Lys Val Cys 1 510 15 Tyr Pro Pro Glu Ser Ser Pro Gln Asn Leu Ala Ala Tyr Tyr Thr Pro 2025 30 Phe Pro Ser Tyr Gly His Tyr Arg Asn Ser Leu Ala Thr Val Glu Glu 3540 45 Asp Phe Gln Pro Phe Arg Gln Leu Glu Ala Ala Ala Ser Ala Ala Pro 5055 60 Ala Met Pro Pro Phe Pro Phe Arg Met Ala Pro Pro Leu Leu Ser Pro 6570 75 80 Gly Leu Gly Leu Gln Arg Glu Pro Leu Tyr Asp Leu Pro Trp Tyr Ser85 90 95 Lys Leu Pro Pro Trp Tyr Pro Ile Pro His Val Pro Arg Glu Val Pro100 105 110 Pro Phe Leu Ser Ser Ser His Glu Tyr Ala Gly Ala Ser Ser GluAsp 115 120 125 Leu Gly His Gln Ile Ile Gly Gly Asp Asn Glu Ser Gly ProCys Cys 130 135 140 Gly Pro Asp Thr Leu Ile Pro Pro Pro Pro Ala Asp AlaSer Leu Leu 145 150 155 160 Pro Glu Gly Leu Arg Thr Ser Gln Leu Leu ProCys Ser Pro Ser Lys 165 170 175 Gln Ser Glu Asp Gly Pro Lys Pro Ser AsnGln Glu Gly Lys Ser Pro 180 185 190 Ala Arg Phe Gln Phe Thr Glu Glu AspLeu His Phe Val Leu Tyr Gly 195 200 205 Val Thr Pro Ser Leu Glu His ProAla Ser Leu His His Ala Ile Ser 210 215 220 Gly Leu Leu Val Pro Pro AspSer Ser Gly Ser Asp Ser Leu Pro Gln 225 230 235 240 Thr Leu Asp Lys AspSer Leu Gln Leu Pro Glu Gly Leu Cys Leu Met 245 250 255 Gln Thr Val PheGly Glu Val Pro His Phe Gly Val Phe Cys Ser Ser 260 265 270 Phe Ile AlaLys Gly Val Arg Phe Gly Pro Phe Gln Gly Lys Val Val 275 280 285 Asn AlaSer Glu Val Lys Thr Tyr Gly Asp Asn Ser Val Met Trp Glu 290 295 300 IlePhe Glu Asp Gly His Leu Ser His Phe Ile Asp Gly Lys Gly Gly 305 310 315320 Thr Gly Asn Trp Met Ser Tyr Val Asn Cys Ala Arg Phe Pro Lys Glu 325330 335 Gln Asn Leu Val Ala Val Gln Cys Gln Gly His Ile Phe Tyr Glu Ser340 345 350 Cys Lys Glu Ile His Gln Asn Gln Glu Leu Leu Val Trp Tyr GlyAsp 355 360 365 Cys Tyr Glu Lys Phe Leu Asp Ile Pro Val Ser Leu Gln ValThr Glu 370 375 380 Pro Gly Lys Gln Pro Ser Gly Pro Ser Glu Glu Ser AlaGlu Gly Tyr 385 390 395 400 Arg Cys Glu Arg Cys Gly Lys Val Phe Thr TyrLys Tyr Tyr Arg Asp 405 410 415 Lys His Leu Lys Tyr Thr Pro Cys Val AspLys Gly Asp Arg Lys Phe 420 425 430 Pro Cys Ser Leu Cys Lys Arg Ser PheGlu Lys Arg Asp Arg Leu Arg 435 440 445 Ile His Ile Leu His Val His GluLys His Arg Pro His Lys Cys Ser 450 455 460 Thr Cys Gly Lys Cys Phe SerGln Ser Ser Ser Leu Asn Lys His Met 465 470 475 480 Arg Val His Ser GlyAsp Arg Pro Tyr Gln Cys Val Tyr Cys Thr Lys 485 490 495 Arg Phe Thr AlaSer Ser Ile Leu Arg Thr His Ile Arg Gln His Ser 500 505 510 Gly Glu LysPro Phe Lys Cys Lys Tyr Cys Gly Lys Ser Phe Ala Ser 515 520 525 His AlaAla His Asp Ser His Val Arg Arg Ser His Lys Glu Asp Asp 530 535 540 GlyCys Ser Cys Ser Ile Cys Gly Lys Ile Phe Ser Asp Gln Glu Thr 545 550 555560 Phe Tyr Ser His Met Lys Phe His Glu Asp Tyr 565 570 13 2965 DNA Homosapiens CDS (112)...(2964) 13 cgctgccccg tccacgccgc ccgcgccccgcagtcccacc cgcaggaccc ccggccgcgc 60 cagggtctcg cctgcgcccc ccgcgcccgcccgcggacta caagtcccgc c atg ccc 117 Met Pro 1 cgc cgc cgc ccc ccg gcttcc ggt gct gcg cag ttt ccg gag cgg atc 165 Arg Arg Arg Pro Pro Ala SerGly Ala Ala Gln Phe Pro Glu Arg Ile 5 10 15 gca acc cgg agt ccg gat ccgatc ccg ctc tgc aca ttc caa agg caa 213 Ala Thr Arg Ser Pro Asp Pro IlePro Leu Cys Thr Phe Gln Arg Gln 20 25 30 ccg cgc gcc gcc ccg gtc cag ccgcca tgc cga ctg ttc ttt gtt aca 261 Pro Arg Ala Ala Pro Val Gln Pro ProCys Arg Leu Phe Phe Val Thr 35 40 45 50 ttc gcc ggc tgc ggg cac cgt tggcga tcg gag tca aaa ccc ggc tgg 309 Phe Ala Gly Cys Gly His Arg Trp ArgSer Glu Ser Lys Pro Gly Trp 55 60 65 att tcc cgg agc cgc tcc ggg atc gccctg cgc gcc gcc cgc ccg ccg 357 Ile Ser Arg Ser Arg Ser Gly Ile Ala LeuArg Ala Ala Arg Pro Pro 70 75 80 ggg tct tcg ccg ccc cgg ccc gcg gcc ccgcgg ccc ccg ccg ccg ggc 405 Gly Ser Ser Pro Pro Arg Pro Ala Ala Pro ArgPro Pro Pro Pro Gly 85 90 95 ggc gtc gtc gcc gag gcc cca ggg gat gtc gttatc ccc cgc cct cgg 453 Gly Val Val Ala Glu Ala Pro Gly Asp Val Val IlePro Arg Pro Arg 100 105 110 gta cag ccc atg cgg gtc gca cgg ggg ggt ccctgg acc ccc aac ccc 501 Val Gln Pro Met Arg Val Ala Arg Gly Gly Pro TrpThr Pro Asn Pro 115 120 125 130 gcg ttt aga gaa gct gag tcc tgg tcc cagatt ggg aac cag agg gtc 549 Ala Phe Arg Glu Ala Glu Ser Trp Ser Gln IleGly Asn Gln Arg Val 135 140 145 agt gag cag ctc ttg gaa aca tct cta gggaat gag gtg tcc gac act 597 Ser Glu Gln Leu Leu Glu Thr Ser Leu Gly AsnGlu Val Ser Asp Thr 150 155 160 gag cca ctg agc cct gcg agt gca ggc ctgcga cgc aat cct gcc cta 645 Glu Pro Leu Ser Pro Ala Ser Ala Gly Leu ArgArg Asn Pro Ala Leu 165 170 175 cct cct gga ccc ttt gca caa aac ttt tcctgg ggg aac cag gaa aat 693 Pro Pro Gly Pro Phe Ala Gln Asn Phe Ser TrpGly Asn Gln Glu Asn 180 185 190 ctg ccc cca gcc ctg ggg aag att gcg aacgga gga gga act ggg gca 741 Leu Pro Pro Ala Leu Gly Lys Ile Ala Asn GlyGly Gly Thr Gly Ala 195 200 205 210 ggc aag gcc gaa tgc ggc tat gaa actgag tca cac ttg cta gag ccg 789 Gly Lys Ala Glu Cys Gly Tyr Glu Thr GluSer His Leu Leu Glu Pro 215 220 225 cac gag ata cct ttg aac gtg aat acacac aag ttc agt gac tgt gag 837 His Glu Ile Pro Leu Asn Val Asn Thr HisLys Phe Ser Asp Cys Glu 230 235 240 ttt cca tat gag ttt tgc acg gtc tgcttt tca ccc ttc aag ctg ctg 885 Phe Pro Tyr Glu Phe Cys Thr Val Cys PheSer Pro Phe Lys Leu Leu 245 250 255 ggg atg agc ggg gtg gag ggc gtg tggaat cag cat tca aga agt gcc 933 Gly Met Ser Gly Val Glu Gly Val Trp AsnGln His Ser Arg Ser Ala 260 265 270 agc atg cac act ttc cta aac cac tcagca acg ggc atc aga gaa gca 981 Ser Met His Thr Phe Leu Asn His Ser AlaThr Gly Ile Arg Glu Ala 275 280 285 290 ggt tgc agg aag gac atg ccc gtgtca gag atg gct gaa gat ggg agc 1029 Gly Cys Arg Lys Asp Met Pro Val SerGlu Met Ala Glu Asp Gly Ser 295 300 305 gaa gag atc atg ttc atc tgg tgtgaa gac tgc agc cag tac cac gac 1077 Glu Glu Ile Met Phe Ile Trp Cys GluAsp Cys Ser Gln Tyr His Asp 310 315 320 tcc gaa tgt ccc gag ctg ggc ccagtg gtc atg gtc aaa gac tcc ttt 1125 Ser Glu Cys Pro Glu Leu Gly Pro ValVal Met Val Lys Asp Ser Phe 325 330 335 gtg tta agc agg gca agg tct tggcct gcc agc gga cac gtg cac acc 1173 Val Leu Ser Arg Ala Arg Ser Trp ProAla Ser Gly His Val His Thr 340 345 350 cag gcg ggg cag ggg atg cgg ggttat gag gac agg gac agg gct gac 1221 Gln Ala Gly Gln Gly Met Arg Gly TyrGlu Asp Arg Asp Arg Ala Asp 355 360 365 370 cca cag cag ctt cca gaa gcagtc cct gca ggc ctg gtg agg cgg ctc 1269 Pro Gln Gln Leu Pro Glu Ala ValPro Ala Gly Leu Val Arg Arg Leu 375 380 385 agt ggg cag cag ctg ccc tgccgt tcc acc ctc acc tgg ggg agg ctg 1317 Ser Gly Gln Gln Leu Pro Cys ArgSer Thr Leu Thr Trp Gly Arg Leu 390 395 400 tgc cac ctg gtg gcc cag ggcagg tca tcc ctt cct ccc aac ttg gag 1365 Cys His Leu Val Ala Gln Gly ArgSer Ser Leu Pro Pro Asn Leu Glu 405 410 415 atc aga cga ctg gaa gat ggagcc gag ggg gtg ttc gcc atc act cag 1413 Ile Arg Arg Leu Glu Asp Gly AlaGlu Gly Val Phe Ala Ile Thr Gln 420 425 430 ctc gtc aag cgg aca cag ttcggt ccc ttt gag tcc agg agg gtc gcc 1461 Leu Val Lys Arg Thr Gln Phe GlyPro Phe Glu Ser Arg Arg Val Ala 435 440 445 450 aaa tgg gaa aag gag tctgca ttt ccc ctg aag gtg ttc cag aag gac 1509 Lys Trp Glu Lys Glu Ser AlaPhe Pro Leu Lys Val Phe Gln Lys Asp 455 460 465 ggg cac ccc gtg tgc ttcgac acc tcc aac gag gat gac tgc aac tgg 1557 Gly His Pro Val Cys Phe AspThr Ser Asn Glu Asp Asp Cys Asn Trp 470 475 480 atg atg ctg gtg cgg ccagcg gcg gag gcc gag cac cag aac ctg acg 1605 Met Met Leu Val Arg Pro AlaAla Glu Ala Glu His Gln Asn Leu Thr 485 490 495 gcc tac cag cac ggc agcgac gtg tac ttc acc acc tcc aga gac atc 1653 Ala Tyr Gln His Gly Ser AspVal Tyr Phe Thr Thr Ser Arg Asp Ile 500 505 510 ccc ccg ggt acc gag ctgcgc gtg tgg tat gcg gcc ttc tat gcc aag 1701 Pro Pro Gly Thr Glu Leu ArgVal Trp Tyr Ala Ala Phe Tyr Ala Lys 515 520 525 530 aag atg gac aag cccatg ctg aag cag gcc ggc tct ggc gtc cac gct 1749 Lys Met Asp Lys Pro MetLeu Lys Gln Ala Gly Ser Gly Val His Ala 535 540 545 gca ggc acc cca gaaaac agc gcc ccc gtg gag tcg gag ccc agc cag 1797 Ala Gly Thr Pro Glu AsnSer Ala Pro Val Glu Ser Glu Pro Ser Gln 550 555 560 tgg gcg tgt aaa gtgtgt tct gcc acc ttc ctg gag ctg cag ctc ctc 1845 Trp Ala Cys Lys Val CysSer Ala Thr Phe Leu Glu Leu Gln Leu Leu 565 570 575 aat gaa cat ctg ttgggc cac tta gaa caa gcc aaa agc ctt cct cca 1893 Asn Glu His Leu Leu GlyHis Leu Glu Gln Ala Lys Ser Leu Pro Pro 580 585 590 ggc agc caa agc gaggca gca gct ccc gag aag gag cag gac aca ccc 1941 Gly Ser Gln Ser Glu AlaAla Ala Pro Glu Lys Glu Gln Asp Thr Pro 595 600 605 610 cgg ggg gaa ccccct gca gtg ccc gag agc gag aat gtt gcc acc aaa 1989 Arg Gly Glu Pro ProAla Val Pro Glu Ser Glu Asn Val Ala Thr Lys 615 620 625 gaa cag aag aaaaag cct cga agg ggg aga aaa ccc aaa gtg tcc aaa 2037 Glu Gln Lys Lys LysPro Arg Arg Gly Arg Lys Pro Lys Val Ser Lys 630 635 640 gct gag cag cctcta gtc atc gtg gaa gac aag gaa ccc aca gag caa 2085 Ala Glu Gln Pro LeuVal Ile Val Glu Asp Lys Glu Pro Thr Glu Gln 645 650 655 gtg gca gag atcatt acc gag gtc cct ccg gat gag cct gtg agt gca 2133 Val Ala Glu Ile IleThr Glu Val Pro Pro Asp Glu Pro Val Ser Ala 660 665 670 acg cca gat gagcgg atc atg gag ctg gtt ctg ggg aag ctg gcc acc 2181 Thr Pro Asp Glu ArgIle Met Glu Leu Val Leu Gly Lys Leu Ala Thr 675 680 685 690 acc acc actgac acc agc tcg gtt cca aag ttc acc cat cat cag aat 2229 Thr Thr Thr AspThr Ser Ser Val Pro Lys Phe Thr His His Gln Asn 695 700 705 aac acc atcacg ctc aag agg agc tta att ctc tca agc aga cac ggc 2277 Asn Thr Ile ThrLeu Lys Arg Ser Leu Ile Leu Ser Ser Arg His Gly 710 715 720 atc cgg cgcaag ctc atc aaa cag ctc ggg gag cac aag cgg gtt tac 2325 Ile Arg Arg LysLeu Ile Lys Gln Leu Gly Glu His Lys Arg Val Tyr 725 730 735 cag tgc aatatc tgc agc aag atc ttc cag aac agc agc aac ctg agc 2373 Gln Cys Asn IleCys Ser Lys Ile Phe Gln Asn Ser Ser Asn Leu Ser 740 745 750 agg cac gtgcgc tcg cat ggt gac aag ctg ttt aag tgc gaa gag tgt 2421 Arg His Val ArgSer His Gly Asp Lys Leu Phe Lys Cys Glu Glu Cys 755 760 765 770 gca aaattg ttc agc cgc aaa gag agc cta aag cag cac gtt tcc tac 2469 Ala Lys LeuPhe Ser Arg Lys Glu Ser Leu Lys Gln His Val Ser Tyr 775 780 785 aag cacagc agg aac gag gtg gac ggc gag tac agg tac cgc tgc ggc 2517 Lys His SerArg Asn Glu Val Asp Gly Glu Tyr Arg Tyr Arg Cys Gly 790 795 800 act tgtgag aag acc ttc cgc atc gag agc gcg ctg gag ttc cac aac 2565 Thr Cys GluLys Thr Phe Arg Ile Glu Ser Ala Leu Glu Phe His Asn 805 810 815 tgc aggaca gat gac aag acg ttc caa tgt gag atg tgt ttc aga ttc 2613 Cys Arg ThrAsp Asp Lys Thr Phe Gln Cys Glu Met Cys Phe Arg Phe 820 825 830 ttc tccacc aac agc aac ctc tcc aag cac aag aag aag cac ggc gac 2661 Phe Ser ThrAsn Ser Asn Leu Ser Lys His Lys Lys Lys His Gly Asp 835 840 845 850 aagaag ttt gcc tgt gag gtc tgc agc aag atg ttc tac cgc aag gac 2709 Lys LysPhe Ala Cys Glu Val Cys Ser Lys Met Phe Tyr Arg Lys Asp 855 860 865 gtcatg ctg gac cac cag cgc cgg cac ctg gaa gga gtg cgg cga gtg 2757 Val MetLeu Asp His Gln Arg Arg His Leu Glu Gly Val Arg Arg Val 870 875 880 aagcga gag gac ctg gag gcc ggt ggg gag aac ctg gtc cgt tac aag 2805 Lys ArgGlu Asp Leu Glu Ala Gly Gly Glu Asn Leu Val Arg Tyr Lys 885 890 895 aaggag cct tcc ggg tgc ccg gtg tgt ggc aag gtg ttc tcc tgc cgg 2853 Lys GluPro Ser Gly Cys Pro Val Cys Gly Lys Val Phe Ser Cys Arg 900 905 910 agcaat atg aac aag cac ctg ctc acc cac ggg gac aag aag tac acc 2901 Ser AsnMet Asn Lys His Leu Leu Thr His Gly Asp Lys Lys Tyr Thr 915 920 925 930tgc gag atc tgc ggg cgc aag ttc ttc cgc gtg gat gtg ctc agg gac 2949 CysGlu Ile Cys Gly Arg Lys Phe Phe Arg Val Asp Val Leu Arg Asp 935 940 945cac atc cat gtc cac t 2965 His Ile His Val His 950 14 951 PRT Homosapiens 14 Met Pro Arg Arg Arg Pro Pro Ala Ser Gly Ala Ala Gln Phe ProGlu 1 5 10 15 Arg Ile Ala Thr Arg Ser Pro Asp Pro Ile Pro Leu Cys ThrPhe Gln 20 25 30 Arg Gln Pro Arg Ala Ala Pro Val Gln Pro Pro Cys Arg LeuPhe Phe 35 40 45 Val Thr Phe Ala Gly Cys Gly His Arg Trp Arg Ser Glu SerLys Pro 50 55 60 Gly Trp Ile Ser Arg Ser Arg Ser Gly Ile Ala Leu Arg AlaAla Arg 65 70 75 80 Pro Pro Gly Ser Ser Pro Pro Arg Pro Ala Ala Pro ArgPro Pro Pro 85 90 95 Pro Gly Gly Val Val Ala Glu Ala Pro Gly Asp Val ValIle Pro Arg 100 105 110 Pro Arg Val Gln Pro Met Arg Val Ala Arg Gly GlyPro Trp Thr Pro 115 120 125 Asn Pro Ala Phe Arg Glu Ala Glu Ser Trp SerGln Ile Gly Asn Gln 130 135 140 Arg Val Ser Glu Gln Leu Leu Glu Thr SerLeu Gly Asn Glu Val Ser 145 150 155 160 Asp Thr Glu Pro Leu Ser Pro AlaSer Ala Gly Leu Arg Arg Asn Pro 165 170 175 Ala Leu Pro Pro Gly Pro PheAla Gln Asn Phe Ser Trp Gly Asn Gln 180 185 190 Glu Asn Leu Pro Pro AlaLeu Gly Lys Ile Ala Asn Gly Gly Gly Thr 195 200 205 Gly Ala Gly Lys AlaGlu Cys Gly Tyr Glu Thr Glu Ser His Leu Leu 210 215 220 Glu Pro His GluIle Pro Leu Asn Val Asn Thr His Lys Phe Ser Asp 225 230 235 240 Cys GluPhe Pro Tyr Glu Phe Cys Thr Val Cys Phe Ser Pro Phe Lys 245 250 255 LeuLeu Gly Met Ser Gly Val Glu Gly Val Trp Asn Gln His Ser Arg 260 265 270Ser Ala Ser Met His Thr Phe Leu Asn His Ser Ala Thr Gly Ile Arg 275 280285 Glu Ala Gly Cys Arg Lys Asp Met Pro Val Ser Glu Met Ala Glu Asp 290295 300 Gly Ser Glu Glu Ile Met Phe Ile Trp Cys Glu Asp Cys Ser Gln Tyr305 310 315 320 His Asp Ser Glu Cys Pro Glu Leu Gly Pro Val Val Met ValLys Asp 325 330 335 Ser Phe Val Leu Ser Arg Ala Arg Ser Trp Pro Ala SerGly His Val 340 345 350 His Thr Gln Ala Gly Gln Gly Met Arg Gly Tyr GluAsp Arg Asp Arg 355 360 365 Ala Asp Pro Gln Gln Leu Pro Glu Ala Val ProAla Gly Leu Val Arg 370 375 380 Arg Leu Ser Gly Gln Gln Leu Pro Cys ArgSer Thr Leu Thr Trp Gly 385 390 395 400 Arg Leu Cys His Leu Val Ala GlnGly Arg Ser Ser Leu Pro Pro Asn 405 410 415 Leu Glu Ile Arg Arg Leu GluAsp Gly Ala Glu Gly Val Phe Ala Ile 420 425 430 Thr Gln Leu Val Lys ArgThr Gln Phe Gly Pro Phe Glu Ser Arg Arg 435 440 445 Val Ala Lys Trp GluLys Glu Ser Ala Phe Pro Leu Lys Val Phe Gln 450 455 460 Lys Asp Gly HisPro Val Cys Phe Asp Thr Ser Asn Glu Asp Asp Cys 465 470 475 480 Asn TrpMet Met Leu Val Arg Pro Ala Ala Glu Ala Glu His Gln Asn 485 490 495 LeuThr Ala Tyr Gln His Gly Ser Asp Val Tyr Phe Thr Thr Ser Arg 500 505 510Asp Ile Pro Pro Gly Thr Glu Leu Arg Val Trp Tyr Ala Ala Phe Tyr 515 520525 Ala Lys Lys Met Asp Lys Pro Met Leu Lys Gln Ala Gly Ser Gly Val 530535 540 His Ala Ala Gly Thr Pro Glu Asn Ser Ala Pro Val Glu Ser Glu Pro545 550 555 560 Ser Gln Trp Ala Cys Lys Val Cys Ser Ala Thr Phe Leu GluLeu Gln 565 570 575 Leu Leu Asn Glu His Leu Leu Gly His Leu Glu Gln AlaLys Ser Leu 580 585 590 Pro Pro Gly Ser Gln Ser Glu Ala Ala Ala Pro GluLys Glu Gln Asp 595 600 605 Thr Pro Arg Gly Glu Pro Pro Ala Val Pro GluSer Glu Asn Val Ala 610 615 620 Thr Lys Glu Gln Lys Lys Lys Pro Arg ArgGly Arg Lys Pro Lys Val 625 630 635 640 Ser Lys Ala Glu Gln Pro Leu ValIle Val Glu Asp Lys Glu Pro Thr 645 650 655 Glu Gln Val Ala Glu Ile IleThr Glu Val Pro Pro Asp Glu Pro Val 660 665 670 Ser Ala Thr Pro Asp GluArg Ile Met Glu Leu Val Leu Gly Lys Leu 675 680 685 Ala Thr Thr Thr ThrAsp Thr Ser Ser Val Pro Lys Phe Thr His His 690 695 700 Gln Asn Asn ThrIle Thr Leu Lys Arg Ser Leu Ile Leu Ser Ser Arg 705 710 715 720 His GlyIle Arg Arg Lys Leu Ile Lys Gln Leu Gly Glu His Lys Arg 725 730 735 ValTyr Gln Cys Asn Ile Cys Ser Lys Ile Phe Gln Asn Ser Ser Asn 740 745 750Leu Ser Arg His Val Arg Ser His Gly Asp Lys Leu Phe Lys Cys Glu 755 760765 Glu Cys Ala Lys Leu Phe Ser Arg Lys Glu Ser Leu Lys Gln His Val 770775 780 Ser Tyr Lys His Ser Arg Asn Glu Val Asp Gly Glu Tyr Arg Tyr Arg785 790 795 800 Cys Gly Thr Cys Glu Lys Thr Phe Arg Ile Glu Ser Ala LeuGlu Phe 805 810 815 His Asn Cys Arg Thr Asp Asp Lys Thr Phe Gln Cys GluMet Cys Phe 820 825 830 Arg Phe Phe Ser Thr Asn Ser Asn Leu Ser Lys HisLys Lys Lys His 835 840 845 Gly Asp Lys Lys Phe Ala Cys Glu Val Cys SerLys Met Phe Tyr Arg 850 855 860 Lys Asp Val Met Leu Asp His Gln Arg ArgHis Leu Glu Gly Val Arg 865 870 875 880 Arg Val Lys Arg Glu Asp Leu GluAla Gly Gly Glu Asn Leu Val Arg 885 890 895 Tyr Lys Lys Glu Pro Ser GlyCys Pro Val Cys Gly Lys Val Phe Ser 900 905 910 Cys Arg Ser Asn Met AsnLys His Leu Leu Thr His Gly Asp Lys Lys 915 920 925 Tyr Thr Cys Glu IleCys Gly Arg Lys Phe Phe Arg Val Asp Val Leu 930 935 940 Arg Asp His IleHis Val His 945 950 15 4376 DNA Homo sapiens CDS (64)...(3837) 15gaagatagtg tgtggctgct tctggactca aggaggagga gagagattcc gcgagccgac 60 accatg cga tcc aag gcg agg gcg agg aag cta gcc aaa agt gac ggt 108 Met ArgSer Lys Ala Arg Ala Arg Lys Leu Ala Lys Ser Asp Gly 1 5 10 15 gac gttgta aat aat atg tat gag ccc aac cgg gac ctg ctg gcc agc 156 Asp Val ValAsn Asn Met Tyr Glu Pro Asn Arg Asp Leu Leu Ala Ser 20 25 30 cac agc gcggag gac gag gcc gag gac agt gcc atg tcg ccc atc ccc 204 His Ser Ala GluAsp Glu Ala Glu Asp Ser Ala Met Ser Pro Ile Pro 35 40 45 gtg ggg tca ccgccc ccc ttc ccc acc agc gag gac ttc acc ccc aag 252 Val Gly Ser Pro ProPro Phe Pro Thr Ser Glu Asp Phe Thr Pro Lys 50 55 60 gag ggc tcg ccg tacgag gcc cct gtc tac att cct gaa gac att ccg 300 Glu Gly Ser Pro Tyr GluAla Pro Val Tyr Ile Pro Glu Asp Ile Pro 65 70 75 atc cca gca gac ttc gagctc cga gag tcc tcc atc cca ggg gct ggc 348 Ile Pro Ala Asp Phe Glu LeuArg Glu Ser Ser Ile Pro Gly Ala Gly 80 85 90 95 ctg ggg gtc tgg gcc aagagg aag atg gaa gcc ggg gag agg ctg ggc 396 Leu Gly Val Trp Ala Lys ArgLys Met Glu Ala Gly Glu Arg Leu Gly 100 105 110 ccc tgc gtg gtg gtg ccccgg gcg gcg gca aag gag aca gac ttc gga 444 Pro Cys Val Val Val Pro ArgAla Ala Ala Lys Glu Thr Asp Phe Gly 115 120 125 tgg gag caa ata ctg acggac gtg gaa gtg tcg ccc cag gaa ggc tgc 492 Trp Glu Gln Ile Leu Thr AspVal Glu Val Ser Pro Gln Glu Gly Cys 130 135 140 atc aca aag atc tcc gaagac ctg ggc agt gag aag ttc tgc gtg gat 540 Ile Thr Lys Ile Ser Glu AspLeu Gly Ser Glu Lys Phe Cys Val Asp 145 150 155 gca aat cag gcg ggg gctggc agc tgg ctc aag tac atc cgt gtg gcg 588 Ala Asn Gln Ala Gly Ala GlySer Trp Leu Lys Tyr Ile Arg Val Ala 160 165 170 175 tgc tcc tgc gat gaccag aac ctc acc atg tgt cag atc agt gag cag 636 Cys Ser Cys Asp Asp GlnAsn Leu Thr Met Cys Gln Ile Ser Glu Gln 180 185 190 gta att tac tat aaagtc att aag gac att gag cca ggt gag gag ctg 684 Val Ile Tyr Tyr Lys ValIle Lys Asp Ile Glu Pro Gly Glu Glu Leu 195 200 205 ctg gtg cac gtg aaggaa ggc gtc tac ccc ctg ggc aca gtg ccg ccc 732 Leu Val His Val Lys GluGly Val Tyr Pro Leu Gly Thr Val Pro Pro 210 215 220 ggc ctg gac gag gagccc acg ttc cgc tgt gac gag tgt gac gaa ctc 780 Gly Leu Asp Glu Glu ProThr Phe Arg Cys Asp Glu Cys Asp Glu Leu 225 230 235 ttc cag tcc aag ctggac ctg cgg cgc cat aag aag tac acg tgt ggc 828 Phe Gln Ser Lys Leu AspLeu Arg Arg His Lys Lys Tyr Thr Cys Gly 240 245 250 255 tca gtg ggg gctgcg ctc tac gag ggc ctg gct gag gag ctc aag ccc 876 Ser Val Gly Ala AlaLeu Tyr Glu Gly Leu Ala Glu Glu Leu Lys Pro 260 265 270 gag ggc ctt ggcggt ggc agc ggc caa gcc cac gag tgc aag gac tgc 924 Glu Gly Leu Gly GlyGly Ser Gly Gln Ala His Glu Cys Lys Asp Cys 275 280 285 gag cgg atg ttcccc aac aag tac agc ctg gag cag cac atg gtc atc 972 Glu Arg Met Phe ProAsn Lys Tyr Ser Leu Glu Gln His Met Val Ile 290 295 300 cac acg gag gagcgc gag tac aaa tgc gac cag tgt ccc aag gcc ttc 1020 His Thr Glu Glu ArgGlu Tyr Lys Cys Asp Gln Cys Pro Lys Ala Phe 305 310 315 aac tgg aag tccaac ttc atc cgc cac cag atg tcc cac gac agc ggc 1068 Asn Trp Lys Ser AsnPhe Ile Arg His Gln Met Ser His Asp Ser Gly 320 325 330 335 aaa cgc ttcgaa tgt gaa aac tgc gtg aag gtg ttc acg gac ccc agc 1116 Lys Arg Phe GluCys Glu Asn Cys Val Lys Val Phe Thr Asp Pro Ser 340 345 350 aac ctt cagcgg cac atc cgc tcg cag cac gtg ggc gct cgg gcc cac 1164 Asn Leu Gln ArgHis Ile Arg Ser Gln His Val Gly Ala Arg Ala His 355 360 365 gcc tgc cccgac tgc ggg aag acc ttc gcc acg tcc tcc ggc ctc aag 1212 Ala Cys Pro AspCys Gly Lys Thr Phe Ala Thr Ser Ser Gly Leu Lys 370 375 380 cag cac aagcat atc cac agc acg gtg aag cct ttc ata tgt gag gtc 1260 Gln His Lys HisIle His Ser Thr Val Lys Pro Phe Ile Cys Glu Val 385 390 395 tgc cac aagtcc tac acg cag ttc tcc aac ctg tgc cgg cac aag cgg 1308 Cys His Lys SerTyr Thr Gln Phe Ser Asn Leu Cys Arg His Lys Arg 400 405 410 415 atg cacgcc gac tgc cgc acg cag atc aag tgc aag gac tgt ggc cag 1356 Met His AlaAsp Cys Arg Thr Gln Ile Lys Cys Lys Asp Cys Gly Gln 420 425 430 atg ttcagc act acc tcc tcc ctc aac aag cac cgg cgc ttc tgc gag 1404 Met Phe SerThr Thr Ser Ser Leu Asn Lys His Arg Arg Phe Cys Glu 435 440 445 ggc aagaac cat tac acg ccg ggc ggc atc ttt gcc ccg ggc ctg ccc 1452 Gly Lys AsnHis Tyr Thr Pro Gly Gly Ile Phe Ala Pro Gly Leu Pro 450 455 460 ttg accccc agc ccc atg atg gac aag gca aaa ccc tcc ccc agc ctc 1500 Leu Thr ProSer Pro Met Met Asp Lys Ala Lys Pro Ser Pro Ser Leu 465 470 475 aat cacgcc agc ctg ggc ttc aac gag tac ttt ccc tac agg ccg cac 1548 Asn His AlaSer Leu Gly Phe Asn Glu Tyr Phe Pro Tyr Arg Pro His 480 485 490 495 ccgggg agc ctg ccc ttc tcc acg gcg cct ccc acg ttc ccc gca ctc 1596 Pro GlySer Leu Pro Phe Ser Thr Ala Pro Pro Thr Phe Pro Ala Leu 500 505 510 accccc ggc ttc ccg ggc atc ttc cct cca tcc ttg tac ccc cgg ccg 1644 Thr ProGly Phe Pro Gly Ile Phe Pro Pro Ser Leu Tyr Pro Arg Pro 515 520 525 cctctg cta cct ccc aca tcg ctg ctc aag agc ccc ctg aac cac acc 1692 Pro LeuLeu Pro Pro Thr Ser Leu Leu Lys Ser Pro Leu Asn His Thr 530 535 540 caggac gcc aag ctc ccc agt ccc ctg ggg aac cca gcc ctg ccc ctg 1740 Gln AspAla Lys Leu Pro Ser Pro Leu Gly Asn Pro Ala Leu Pro Leu 545 550 555 gtctcc gcc gtc agc aac agc agc cag ggc acg acg gca gct gcg ggg 1788 Val SerAla Val Ser Asn Ser Ser Gln Gly Thr Thr Ala Ala Ala Gly 560 565 570 575ccc gag gag aag ttc gag agc cgc ctg gag gac tcc tgt gtg gag aag 1836 ProGlu Glu Lys Phe Glu Ser Arg Leu Glu Asp Ser Cys Val Glu Lys 580 585 590ctg aag acc agg agc agc gac atg tcg gac ggc agt gac ttt gag gac 1884 LeuLys Thr Arg Ser Ser Asp Met Ser Asp Gly Ser Asp Phe Glu Asp 595 600 605gtc aac acc acc acg ggg acc gac ctg gac acg acc acg ggg acg ggc 1932 ValAsn Thr Thr Thr Gly Thr Asp Leu Asp Thr Thr Thr Gly Thr Gly 610 615 620tcg gac ctg gac agc gac gtg gac agc gac cct gac aag gac aag ggc 1980 SerAsp Leu Asp Ser Asp Val Asp Ser Asp Pro Asp Lys Asp Lys Gly 625 630 635aag ggc aag tcc gcc gag ggc cag ccc aag ttt ggg ggc ggc ttg gcg 2028 LysGly Lys Ser Ala Glu Gly Gln Pro Lys Phe Gly Gly Gly Leu Ala 640 645 650655 ccc ccg ggg gcc ccg aac agc gtg gcc gag gtg cct gtc ttc tat tcc 2076Pro Pro Gly Ala Pro Asn Ser Val Ala Glu Val Pro Val Phe Tyr Ser 660 665670 cag cac tca ttc ttc ccg cca ccc gac gag cag ctg ctg act gca acg 2124Gln His Ser Phe Phe Pro Pro Pro Asp Glu Gln Leu Leu Thr Ala Thr 675 680685 ggc gcc gcc ggg gac tcc atc aag gcc atc gca tcc att gcc gag aag 2172Gly Ala Ala Gly Asp Ser Ile Lys Ala Ile Ala Ser Ile Ala Glu Lys 690 695700 tac ttt ggc ccc ggc ttc atg ggg atg cag gag aag aag ctg ggc tcg 2220Tyr Phe Gly Pro Gly Phe Met Gly Met Gln Glu Lys Lys Leu Gly Ser 705 710715 ctc ccc tac cac tcg gcg ttc ccc ttc cag ttc ctg ccc aac ttc ccc 2268Leu Pro Tyr His Ser Ala Phe Pro Phe Gln Phe Leu Pro Asn Phe Pro 720 725730 735 cac tcc ctt tac ccc ttc acg gac cga gcc ctc gcc cac aac ttg ctg2316 His Ser Leu Tyr Pro Phe Thr Asp Arg Ala Leu Ala His Asn Leu Leu 740745 750 gtc aag gcc gag cca aag tca ccc cgg gac gcc ctc aag gtg ggc ggc2364 Val Lys Ala Glu Pro Lys Ser Pro Arg Asp Ala Leu Lys Val Gly Gly 755760 765 ccc agt gcc gag tgc ccc ttt gat ctc acc acc aag ccc aaa gac gtg2412 Pro Ser Ala Glu Cys Pro Phe Asp Leu Thr Thr Lys Pro Lys Asp Val 770775 780 aag ccc atc ctg ccc atg ccc aag ggc ccc tcg gcc ccc gca tcc ggc2460 Lys Pro Ile Leu Pro Met Pro Lys Gly Pro Ser Ala Pro Ala Ser Gly 785790 795 gag gag cag ccg ctg gac ctg agc atc ggc agc cgg gcc cgt gcc agc2508 Glu Glu Gln Pro Leu Asp Leu Ser Ile Gly Ser Arg Ala Arg Ala Ser 800805 810 815 caa aac ggc ggc ggg cgg gag ccc cgc aag aac cac gtc tat ggggaa 2556 Gln Asn Gly Gly Gly Arg Glu Pro Arg Lys Asn His Val Tyr Gly Glu820 825 830 cgc aag ctg ggc gcc ggc gag ggg ctg ccc cag gtg tgc ccg gcgcgg 2604 Arg Lys Leu Gly Ala Gly Glu Gly Leu Pro Gln Val Cys Pro Ala Arg835 840 845 atg ccc cag cag ccc ccg ctc cac tac gcc aag ccc tcg ccc ttcttc 2652 Met Pro Gln Gln Pro Pro Leu His Tyr Ala Lys Pro Ser Pro Phe Phe850 855 860 atg gac ccc atc tac agg gta gaa aag cgg aag gtc aca gac cccgtg 2700 Met Asp Pro Ile Tyr Arg Val Glu Lys Arg Lys Val Thr Asp Pro Val865 870 875 gga gcc ctg aag gag aag tac ctg cgg ccg tcc ccg ctg ctc ttccac 2748 Gly Ala Leu Lys Glu Lys Tyr Leu Arg Pro Ser Pro Leu Leu Phe His880 885 890 895 ccc cag atg tca gcc ata gag acc atg aca gag aag ctg gagagc ttt 2796 Pro Gln Met Ser Ala Ile Glu Thr Met Thr Glu Lys Leu Glu SerPhe 900 905 910 gca gcc atg aag gcg gac tcg ggc agc tcc ctg cag ccc ctcccc cac 2844 Ala Ala Met Lys Ala Asp Ser Gly Ser Ser Leu Gln Pro Leu ProHis 915 920 925 cac ccc ttc aac ttc cgg tcc cca ccc cca acg ctc tcc gacccc atc 2892 His Pro Phe Asn Phe Arg Ser Pro Pro Pro Thr Leu Ser Asp ProIle 930 935 940 ctc agg aag ggc aag gag cga tac acg tgc agg tac tgt gggaag atc 2940 Leu Arg Lys Gly Lys Glu Arg Tyr Thr Cys Arg Tyr Cys Gly LysIle 945 950 955 ttc ccc aga tca gcc aat ctc acc aga cac ctg agg acg cacact ggg 2988 Phe Pro Arg Ser Ala Asn Leu Thr Arg His Leu Arg Thr His ThrGly 960 965 970 975 gag cag ccg tac agg tgt aag tac tgc gac cgc tcc ttcagc atc tct 3036 Glu Gln Pro Tyr Arg Cys Lys Tyr Cys Asp Arg Ser Phe SerIle Ser 980 985 990 tcg aac ctc cag cgg cac gtc cgg aac atc cac aac aaggag aag cct 3084 Ser Asn Leu Gln Arg His Val Arg Asn Ile His Asn Lys GluLys Pro 995 1000 1005 ttc aag tgc cac ctg tgc aac cgc tgc ttc ggg cagcag acc aac ctg 3132 Phe Lys Cys His Leu Cys Asn Arg Cys Phe Gly Gln GlnThr Asn Leu 1010 1015 1020 gac cgg cac ctc aag aag cac gag cac gag aacgca cca gtg agc cag 3180 Asp Arg His Leu Lys Lys His Glu His Glu Asn AlaPro Val Ser Gln 1025 1030 1035 cac ccc ggg gtc ctc acg aac cac ctg gggacc agc gcg tcc tct ccc 3228 His Pro Gly Val Leu Thr Asn His Leu Gly ThrSer Ala Ser Ser Pro 1040 1045 1050 1055 acc tca gag tcg gac aac cac gcactt tta gac gag aaa gaa gac tct 3276 Thr Ser Glu Ser Asp Asn His Ala LeuLeu Asp Glu Lys Glu Asp Ser 1060 1065 1070 tat ttc tcg gaa atc aga aacttt att gcc aat agt gag atg aac caa 3324 Tyr Phe Ser Glu Ile Arg Asn PheIle Ala Asn Ser Glu Met Asn Gln 1075 1080 1085 gca tca acg cga aca gagaaa cgg gcg gac atg cag atc gtg gac ggc 3372 Ala Ser Thr Arg Thr Glu LysArg Ala Asp Met Gln Ile Val Asp Gly 1090 1095 1100 agt gcc cag tgt ccaggc cta gcc agt gag aag cag gag gac gtg gag 3420 Ser Ala Gln Cys Pro GlyLeu Ala Ser Glu Lys Gln Glu Asp Val Glu 1105 1110 1115 gag gag gac gacgat gac ctg gag gag gac gat gag gac agc ctg gcc 3468 Glu Glu Asp Asp AspAsp Leu Glu Glu Asp Asp Glu Asp Ser Leu Ala 1120 1125 1130 1135 ggg aagtcg cag gat gac acc gtg tcc ccc gca ccc gag ccc cag gcc 3516 Gly Lys SerGln Asp Asp Thr Val Ser Pro Ala Pro Glu Pro Gln Ala 1140 1145 1150 gcctac gag gat gag gag gat gag gag cca gcc gcc tcc ctg gcc gtg 3564 Ala TyrGlu Asp Glu Glu Asp Glu Glu Pro Ala Ala Ser Leu Ala Val 1155 1160 1165ggc ttt gac cac acc cga agg tgt gct gag gac cac gaa ggc ggt ctg 3612 GlyPhe Asp His Thr Arg Arg Cys Ala Glu Asp His Glu Gly Gly Leu 1170 11751180 tta gct ttg gag ccg atg ccg act ttt ggg aag ggg ctg gac ctc cgc3660 Leu Ala Leu Glu Pro Met Pro Thr Phe Gly Lys Gly Leu Asp Leu Arg1185 1190 1195 aga gca gct gag gaa gca ttt gaa gtt aaa gat gtg ctt aattcc acc 3708 Arg Ala Ala Glu Glu Ala Phe Glu Val Lys Asp Val Leu Asn SerThr 1200 1205 1210 1215 tta gat tct gag gct tta aaa cat aca ctg tgc aggcag gct aag aac 3756 Leu Asp Ser Glu Ala Leu Lys His Thr Leu Cys Arg GlnAla Lys Asn 1220 1225 1230 cag gca tat gca atg atg ctg tcc ctt tcc gaagac act cct ctc cac 3804 Gln Ala Tyr Ala Met Met Leu Ser Leu Ser Glu AspThr Pro Leu His 1235 1240 1245 acc ccc tcc cag ggt tct ctg gac gct tggttg aaggtcactg gagccacgtc 3857 Thr Pro Ser Gln Gly Ser Leu Asp Ala TrpLeu 1250 1255 ggagtctgga gcatttcacc ccatcaacca cctctgacgg gctgggcagccgggggccgg 3917 tggccagagc gagggcacca gccacgaagg acggaggcgg gcggggccccggagaaccct 3977 gtccctgcgt gtggccactc ctcagcatcc tccccaccca ccatggttcattccgacttt 4037 tccaatggaa actcagatcc caaaagtccc taaagcagtc gtagagtctcaccatctcca 4097 aggattggtc ttgagaacac tgttcagtga cggccatgca ggtggccgtccaaagacagc 4157 caacggagct gcctcgcaga atcagccagt gggcaggtgg acgctctgctgagacagaag 4217 ctggtggcca ctgccgggtg cccgcgtggg gtcgcggaag ggaatggatagactggtgtg 4277 ctcaaaagag agagatcact caaatgattt ttataatgaa atgacaagaataaccctttt 4337 ggtaaccgta ttgactgcag agtctattta agcatgtgg 4376 16 1258PRT Homo sapiens 16 Met Arg Ser Lys Ala Arg Ala Arg Lys Leu Ala Lys SerAsp Gly Asp 1 5 10 15 Val Val Asn Asn Met Tyr Glu Pro Asn Arg Asp LeuLeu Ala Ser His 20 25 30 Ser Ala Glu Asp Glu Ala Glu Asp Ser Ala Met SerPro Ile Pro Val 35 40 45 Gly Ser Pro Pro Pro Phe Pro Thr Ser Glu Asp PheThr Pro Lys Glu 50 55 60 Gly Ser Pro Tyr Glu Ala Pro Val Tyr Ile Pro GluAsp Ile Pro Ile 65 70 75 80 Pro Ala Asp Phe Glu Leu Arg Glu Ser Ser IlePro Gly Ala Gly Leu 85 90 95 Gly Val Trp Ala Lys Arg Lys Met Glu Ala GlyGlu Arg Leu Gly Pro 100 105 110 Cys Val Val Val Pro Arg Ala Ala Ala LysGlu Thr Asp Phe Gly Trp 115 120 125 Glu Gln Ile Leu Thr Asp Val Glu ValSer Pro Gln Glu Gly Cys Ile 130 135 140 Thr Lys Ile Ser Glu Asp Leu GlySer Glu Lys Phe Cys Val Asp Ala 145 150 155 160 Asn Gln Ala Gly Ala GlySer Trp Leu Lys Tyr Ile Arg Val Ala Cys 165 170 175 Ser Cys Asp Asp GlnAsn Leu Thr Met Cys Gln Ile Ser Glu Gln Val 180 185 190 Ile Tyr Tyr LysVal Ile Lys Asp Ile Glu Pro Gly Glu Glu Leu Leu 195 200 205 Val His ValLys Glu Gly Val Tyr Pro Leu Gly Thr Val Pro Pro Gly 210 215 220 Leu AspGlu Glu Pro Thr Phe Arg Cys Asp Glu Cys Asp Glu Leu Phe 225 230 235 240Gln Ser Lys Leu Asp Leu Arg Arg His Lys Lys Tyr Thr Cys Gly Ser 245 250255 Val Gly Ala Ala Leu Tyr Glu Gly Leu Ala Glu Glu Leu Lys Pro Glu 260265 270 Gly Leu Gly Gly Gly Ser Gly Gln Ala His Glu Cys Lys Asp Cys Glu275 280 285 Arg Met Phe Pro Asn Lys Tyr Ser Leu Glu Gln His Met Val IleHis 290 295 300 Thr Glu Glu Arg Glu Tyr Lys Cys Asp Gln Cys Pro Lys AlaPhe Asn 305 310 315 320 Trp Lys Ser Asn Phe Ile Arg His Gln Met Ser HisAsp Ser Gly Lys 325 330 335 Arg Phe Glu Cys Glu Asn Cys Val Lys Val PheThr Asp Pro Ser Asn 340 345 350 Leu Gln Arg His Ile Arg Ser Gln His ValGly Ala Arg Ala His Ala 355 360 365 Cys Pro Asp Cys Gly Lys Thr Phe AlaThr Ser Ser Gly Leu Lys Gln 370 375 380 His Lys His Ile His Ser Thr ValLys Pro Phe Ile Cys Glu Val Cys 385 390 395 400 His Lys Ser Tyr Thr GlnPhe Ser Asn Leu Cys Arg His Lys Arg Met 405 410 415 His Ala Asp Cys ArgThr Gln Ile Lys Cys Lys Asp Cys Gly Gln Met 420 425 430 Phe Ser Thr ThrSer Ser Leu Asn Lys His Arg Arg Phe Cys Glu Gly 435 440 445 Lys Asn HisTyr Thr Pro Gly Gly Ile Phe Ala Pro Gly Leu Pro Leu 450 455 460 Thr ProSer Pro Met Met Asp Lys Ala Lys Pro Ser Pro Ser Leu Asn 465 470 475 480His Ala Ser Leu Gly Phe Asn Glu Tyr Phe Pro Tyr Arg Pro His Pro 485 490495 Gly Ser Leu Pro Phe Ser Thr Ala Pro Pro Thr Phe Pro Ala Leu Thr 500505 510 Pro Gly Phe Pro Gly Ile Phe Pro Pro Ser Leu Tyr Pro Arg Pro Pro515 520 525 Leu Leu Pro Pro Thr Ser Leu Leu Lys Ser Pro Leu Asn His ThrGln 530 535 540 Asp Ala Lys Leu Pro Ser Pro Leu Gly Asn Pro Ala Leu ProLeu Val 545 550 555 560 Ser Ala Val Ser Asn Ser Ser Gln Gly Thr Thr AlaAla Ala Gly Pro 565 570 575 Glu Glu Lys Phe Glu Ser Arg Leu Glu Asp SerCys Val Glu Lys Leu 580 585 590 Lys Thr Arg Ser Ser Asp Met Ser Asp GlySer Asp Phe Glu Asp Val 595 600 605 Asn Thr Thr Thr Gly Thr Asp Leu AspThr Thr Thr Gly Thr Gly Ser 610 615 620 Asp Leu Asp Ser Asp Val Asp SerAsp Pro Asp Lys Asp Lys Gly Lys 625 630 635 640 Gly Lys Ser Ala Glu GlyGln Pro Lys Phe Gly Gly Gly Leu Ala Pro 645 650 655 Pro Gly Ala Pro AsnSer Val Ala Glu Val Pro Val Phe Tyr Ser Gln 660 665 670 His Ser Phe PhePro Pro Pro Asp Glu Gln Leu Leu Thr Ala Thr Gly 675 680 685 Ala Ala GlyAsp Ser Ile Lys Ala Ile Ala Ser Ile Ala Glu Lys Tyr 690 695 700 Phe GlyPro Gly Phe Met Gly Met Gln Glu Lys Lys Leu Gly Ser Leu 705 710 715 720Pro Tyr His Ser Ala Phe Pro Phe Gln Phe Leu Pro Asn Phe Pro His 725 730735 Ser Leu Tyr Pro Phe Thr Asp Arg Ala Leu Ala His Asn Leu Leu Val 740745 750 Lys Ala Glu Pro Lys Ser Pro Arg Asp Ala Leu Lys Val Gly Gly Pro755 760 765 Ser Ala Glu Cys Pro Phe Asp Leu Thr Thr Lys Pro Lys Asp ValLys 770 775 780 Pro Ile Leu Pro Met Pro Lys Gly Pro Ser Ala Pro Ala SerGly Glu 785 790 795 800 Glu Gln Pro Leu Asp Leu Ser Ile Gly Ser Arg AlaArg Ala Ser Gln 805 810 815 Asn Gly Gly Gly Arg Glu Pro Arg Lys Asn HisVal Tyr Gly Glu Arg 820 825 830 Lys Leu Gly Ala Gly Glu Gly Leu Pro GlnVal Cys Pro Ala Arg Met 835 840 845 Pro Gln Gln Pro Pro Leu His Tyr AlaLys Pro Ser Pro Phe Phe Met 850 855 860 Asp Pro Ile Tyr Arg Val Glu LysArg Lys Val Thr Asp Pro Val Gly 865 870 875 880 Ala Leu Lys Glu Lys TyrLeu Arg Pro Ser Pro Leu Leu Phe His Pro 885 890 895 Gln Met Ser Ala IleGlu Thr Met Thr Glu Lys Leu Glu Ser Phe Ala 900 905 910 Ala Met Lys AlaAsp Ser Gly Ser Ser Leu Gln Pro Leu Pro His His 915 920 925 Pro Phe AsnPhe Arg Ser Pro Pro Pro Thr Leu Ser Asp Pro Ile Leu 930 935 940 Arg LysGly Lys Glu Arg Tyr Thr Cys Arg Tyr Cys Gly Lys Ile Phe 945 950 955 960Pro Arg Ser Ala Asn Leu Thr Arg His Leu Arg Thr His Thr Gly Glu 965 970975 Gln Pro Tyr Arg Cys Lys Tyr Cys Asp Arg Ser Phe Ser Ile Ser Ser 980985 990 Asn Leu Gln Arg His Val Arg Asn Ile His Asn Lys Glu Lys Pro Phe995 1000 1005 Lys Cys His Leu Cys Asn Arg Cys Phe Gly Gln Gln Thr AsnLeu Asp 1010 1015 1020 Arg His Leu Lys Lys His Glu His Glu Asn Ala ProVal Ser Gln His 1025 1030 1035 1040 Pro Gly Val Leu Thr Asn His Leu GlyThr Ser Ala Ser Ser Pro Thr 1045 1050 1055 Ser Glu Ser Asp Asn His AlaLeu Leu Asp Glu Lys Glu Asp Ser Tyr 1060 1065 1070 Phe Ser Glu Ile ArgAsn Phe Ile Ala Asn Ser Glu Met Asn Gln Ala 1075 1080 1085 Ser Thr ArgThr Glu Lys Arg Ala Asp Met Gln Ile Val Asp Gly Ser 1090 1095 1100 AlaGln Cys Pro Gly Leu Ala Ser Glu Lys Gln Glu Asp Val Glu Glu 1105 11101115 1120 Glu Asp Asp Asp Asp Leu Glu Glu Asp Asp Glu Asp Ser Leu AlaGly 1125 1130 1135 Lys Ser Gln Asp Asp Thr Val Ser Pro Ala Pro Glu ProGln Ala Ala 1140 1145 1150 Tyr Glu Asp Glu Glu Asp Glu Glu Pro Ala AlaSer Leu Ala Val Gly 1155 1160 1165 Phe Asp His Thr Arg Arg Cys Ala GluAsp His Glu Gly Gly Leu Leu 1170 1175 1180 Ala Leu Glu Pro Met Pro ThrPhe Gly Lys Gly Leu Asp Leu Arg Arg 1185 1190 1195 1200 Ala Ala Glu GluAla Phe Glu Val Lys Asp Val Leu Asn Ser Thr Leu 1205 1210 1215 Asp SerGlu Ala Leu Lys His Thr Leu Cys Arg Gln Ala Lys Asn Gln 1220 1225 1230Ala Tyr Ala Met Met Leu Ser Leu Ser Glu Asp Thr Pro Leu His Thr 12351240 1245 Pro Ser Gln Gly Ser Leu Asp Ala Trp Leu 1250 1255 17 2442 DNAHomo sapiens CDS (232)...(2391) 17 agctttccca gctagtcgaa tcactggtgcacctccggaa tccgaggttc gcattgctct 60 cggacagagt tctgcctccc cagtactcccaaactcccag tcctgtgcac caatgaggtc 120 cagctctgag gcttctttcc tgagaaaaaaatttggaagt ccgtgactgt ttcctggagg 180 agctgagaag aggaagctca cttccggcgtagggaggctt tctgacccgg a atg gag 237 Met Glu 1 gag gcg gag gag ctg ctcttg gag ggg aag aag gcg ctg caa ctc gcc 285 Glu Ala Glu Glu Leu Leu LeuGlu Gly Lys Lys Ala Leu Gln Leu Ala 5 10 15 cgc gag ccg cgc ctg ggc ctggac tta gga tgg aac cct tcc gga gaa 333 Arg Glu Pro Arg Leu Gly Leu AspLeu Gly Trp Asn Pro Ser Gly Glu 20 25 30 ggc tgt acg cag ggc ctc aaa gacgtc cca ccc gag ccg acc cga gac 381 Gly Cys Thr Gln Gly Leu Lys Asp ValPro Pro Glu Pro Thr Arg Asp 35 40 45 50 atc ctc gct tta aag agc ctt ccccgg ggc ttg gcc ctt ggc ccc tca 429 Ile Leu Ala Leu Lys Ser Leu Pro ArgGly Leu Ala Leu Gly Pro Ser 55 60 65 ctc gcc aag gaa cag cgc ttg ggg gtctgg tgt gtc ggg gac ccc ctg 477 Leu Ala Lys Glu Gln Arg Leu Gly Val TrpCys Val Gly Asp Pro Leu 70 75 80 cag ccc ggc ctg ctg tgg ggg ccg ctg gaagag gag tct gcc tcc aag 525 Gln Pro Gly Leu Leu Trp Gly Pro Leu Glu GluGlu Ser Ala Ser Lys 85 90 95 gag aag ggc gag gga gta aag cca cgg cag gaggag aac ctg tca tta 573 Glu Lys Gly Glu Gly Val Lys Pro Arg Gln Glu GluAsn Leu Ser Leu 100 105 110 ggc cca tgg gga gac gtg tgt gcc tgt gag cagagt tct ggc tgg act 621 Gly Pro Trp Gly Asp Val Cys Ala Cys Glu Gln SerSer Gly Trp Thr 115 120 125 130 agc ttg gta caa cgg ggc agg ctg gag agtgag gga aat gtg gcc cca 669 Ser Leu Val Gln Arg Gly Arg Leu Glu Ser GluGly Asn Val Ala Pro 135 140 145 gtg cgg atc agc gag agg ctt cat ctg caagtg tac cag ctg gtg ctg 717 Val Arg Ile Ser Glu Arg Leu His Leu Gln ValTyr Gln Leu Val Leu 150 155 160 cca ggc tct gaa ctg ctg ctg tgg ccc cagcct tcc tct gag ggc cca 765 Pro Gly Ser Glu Leu Leu Leu Trp Pro Gln ProSer Ser Glu Gly Pro 165 170 175 agt ctc acc cag cct ggg ctg gac aaa gaggca gct gta gca gtg gtg 813 Ser Leu Thr Gln Pro Gly Leu Asp Lys Glu AlaAla Val Ala Val Val 180 185 190 aca gaa gtg gag tct gct gta cag cag gaagtg gcc tcc cct ggg gag 861 Thr Glu Val Glu Ser Ala Val Gln Gln Glu ValAla Ser Pro Gly Glu 195 200 205 210 gat gca gca gaa cct tgc ata gat cctggt tcc cag tca ccc tct ggc 909 Asp Ala Ala Glu Pro Cys Ile Asp Pro GlySer Gln Ser Pro Ser Gly 215 220 225 atc cag gca gag aat atg gtg agc cctgga ctt aag ttc cca acc cag 957 Ile Gln Ala Glu Asn Met Val Ser Pro GlyLeu Lys Phe Pro Thr Gln 230 235 240 gac cga att tcc aag gat agc cag ccactt ggc cca ttg ctt cag gat 1005 Asp Arg Ile Ser Lys Asp Ser Gln Pro LeuGly Pro Leu Leu Gln Asp 245 250 255 ggc gac gtg gat gag gaa tgc ccg gcccag gca cag atg cca cct gaa 1053 Gly Asp Val Asp Glu Glu Cys Pro Ala GlnAla Gln Met Pro Pro Glu 260 265 270 ctt cag agc aat tcg gct acc cag caggac cca gat ggc agt gga gcc 1101 Leu Gln Ser Asn Ser Ala Thr Gln Gln AspPro Asp Gly Ser Gly Ala 275 280 285 290 agt ttc tca tct tct gcc agg ggcacc cag ccg cat ggc tac ctg gcc 1149 Ser Phe Ser Ser Ser Ala Arg Gly ThrGln Pro His Gly Tyr Leu Ala 295 300 305 aag aag tta cac agc ccc agt gatcag tgc cca ccc aga gca aag acc 1197 Lys Lys Leu His Ser Pro Ser Asp GlnCys Pro Pro Arg Ala Lys Thr 310 315 320 cca gag cct gga gcc cag cag tctggc ttc cct aca ctc tcg cgg agc 1245 Pro Glu Pro Gly Ala Gln Gln Ser GlyPhe Pro Thr Leu Ser Arg Ser 325 330 335 cct cct ggc cca gca gga agc tcccca aag cag ggg cga cgg tac cgg 1293 Pro Pro Gly Pro Ala Gly Ser Ser ProLys Gln Gly Arg Arg Tyr Arg 340 345 350 tgt gga gag tgt ggc aag gca ttccta cag ctg tgc cac cta aag aag 1341 Cys Gly Glu Cys Gly Lys Ala Phe LeuGln Leu Cys His Leu Lys Lys 355 360 365 370 cac gca ttt gtg cac acg ggccac aag ccc ttt ctt tgc act gag tgt 1389 His Ala Phe Val His Thr Gly HisLys Pro Phe Leu Cys Thr Glu Cys 375 380 385 ggc aag agc tat agc tca gaggag agc ttc aaa gcc cat atg ctg ggc 1437 Gly Lys Ser Tyr Ser Ser Glu GluSer Phe Lys Ala His Met Leu Gly 390 395 400 cac cgt ggg gtg cgg ccc ttcccc tgt cca caa tgc gac aag gcc tat 1485 His Arg Gly Val Arg Pro Phe ProCys Pro Gln Cys Asp Lys Ala Tyr 405 410 415 ggc acc cag cga gac ctc aaagag cac cag gtg gta cat tca ggt gcc 1533 Gly Thr Gln Arg Asp Leu Lys GluHis Gln Val Val His Ser Gly Ala 420 425 430 cgg ccc ttt gct tgt gac cagtgt ggc aag gcc ttt gcc cgc cgg ccc 1581 Arg Pro Phe Ala Cys Asp Gln CysGly Lys Ala Phe Ala Arg Arg Pro 435 440 445 450 tcc ctg cgg ctg cat cgcaag acc cac cag gtg cca gct gcc cct gcc 1629 Ser Leu Arg Leu His Arg LysThr His Gln Val Pro Ala Ala Pro Ala 455 460 465 cct tgc cca tgc cct gtgtgt ggg cgg ccc ctg gcc aac cag ggc tcc 1677 Pro Cys Pro Cys Pro Val CysGly Arg Pro Leu Ala Asn Gln Gly Ser 470 475 480 ctg cgg aac cat atg aggctc cat aca gga gaa aag cct ttc ctg tgc 1725 Leu Arg Asn His Met Arg LeuHis Thr Gly Glu Lys Pro Phe Leu Cys 485 490 495 ccg cac tgt ggc cgg gcgttt cgt cag cgg ggc aac ctg cgt ggg cat 1773 Pro His Cys Gly Arg Ala PheArg Gln Arg Gly Asn Leu Arg Gly His 500 505 510 ttg cgg ctc cac acc ggggag cgt cct tac cgc tgc cca cac tgt gcc 1821 Leu Arg Leu His Thr Gly GluArg Pro Tyr Arg Cys Pro His Cys Ala 515 520 525 530 gat gcc ttc ccc cagctg cct gaa ctg cgg cgc cat ctc atc tca cac 1869 Asp Ala Phe Pro Gln LeuPro Glu Leu Arg Arg His Leu Ile Ser His 535 540 545 acc ggg gag gcc cacttg tgc ccg gtg tgt ggc aag gcc ctc cga gac 1917 Thr Gly Glu Ala His LeuCys Pro Val Cys Gly Lys Ala Leu Arg Asp 550 555 560 cca cac acg ctc cgagct cac gag cgt ctg cac tcc gga gag agg ccc 1965 Pro His Thr Leu Arg AlaHis Glu Arg Leu His Ser Gly Glu Arg Pro 565 570 575 ttt ccc tgt ccc cagtgt ggc cgt gct tac acg ctg gcc acc aag ctg 2013 Phe Pro Cys Pro Gln CysGly Arg Ala Tyr Thr Leu Ala Thr Lys Leu 580 585 590 cgg cgc cac ctc aaatct cac ttg gag gac aag ccc tac cgc tgc ccc 2061 Arg Arg His Leu Lys SerHis Leu Glu Asp Lys Pro Tyr Arg Cys Pro 595 600 605 610 acc tgt ggc atgggc tac acc ctc ccg cag agc ctc agg cgg cat cag 2109 Thr Cys Gly Met GlyTyr Thr Leu Pro Gln Ser Leu Arg Arg His Gln 615 620 625 ctc agt cac cggcct gag gca ccc tgc agc cca ccc tct gtg cct tct 2157 Leu Ser His Arg ProGlu Ala Pro Cys Ser Pro Pro Ser Val Pro Ser 630 635 640 gct gct tct gagccc act gtg gtg ctc ctg cag gct gag cca caa ctg 2205 Ala Ala Ser Glu ProThr Val Val Leu Leu Gln Ala Glu Pro Gln Leu 645 650 655 ctg gac aca cacaga gag gag gaa gtc tcc ccc gcc agg gat gtt gtt 2253 Leu Asp Thr His ArgGlu Glu Glu Val Ser Pro Ala Arg Asp Val Val 660 665 670 gag gtc acc atttca gaa agc cag gag aag tgc ttt gtg gtg cca gag 2301 Glu Val Thr Ile SerGlu Ser Gln Glu Lys Cys Phe Val Val Pro Glu 675 680 685 690 gag cca gatgcc gcc ccc agc ctg gtg cta atc cat aag gac atg ggc 2349 Glu Pro Asp AlaAla Pro Ser Leu Val Leu Ile His Lys Asp Met Gly 695 700 705 ctc ggc gcctgg gca gag gtg gtg gag gtg gag atg ggc acc 2391 Leu Gly Ala Trp Ala GluVal Val Glu Val Glu Met Gly Thr 710 715 720 tgacagcttt gccttttgctgacacagctc cataaagact cgtgctttct c 2442 18 720 PRT Homo sapiens 18 MetGlu Glu Ala Glu Glu Leu Leu Leu Glu Gly Lys Lys Ala Leu Gln 1 5 10 15Leu Ala Arg Glu Pro Arg Leu Gly Leu Asp Leu Gly Trp Asn Pro Ser 20 25 30Gly Glu Gly Cys Thr Gln Gly Leu Lys Asp Val Pro Pro Glu Pro Thr 35 40 45Arg Asp Ile Leu Ala Leu Lys Ser Leu Pro Arg Gly Leu Ala Leu Gly 50 55 60Pro Ser Leu Ala Lys Glu Gln Arg Leu Gly Val Trp Cys Val Gly Asp 65 70 7580 Pro Leu Gln Pro Gly Leu Leu Trp Gly Pro Leu Glu Glu Glu Ser Ala 85 9095 Ser Lys Glu Lys Gly Glu Gly Val Lys Pro Arg Gln Glu Glu Asn Leu 100105 110 Ser Leu Gly Pro Trp Gly Asp Val Cys Ala Cys Glu Gln Ser Ser Gly115 120 125 Trp Thr Ser Leu Val Gln Arg Gly Arg Leu Glu Ser Glu Gly AsnVal 130 135 140 Ala Pro Val Arg Ile Ser Glu Arg Leu His Leu Gln Val TyrGln Leu 145 150 155 160 Val Leu Pro Gly Ser Glu Leu Leu Leu Trp Pro GlnPro Ser Ser Glu 165 170 175 Gly Pro Ser Leu Thr Gln Pro Gly Leu Asp LysGlu Ala Ala Val Ala 180 185 190 Val Val Thr Glu Val Glu Ser Ala Val GlnGln Glu Val Ala Ser Pro 195 200 205 Gly Glu Asp Ala Ala Glu Pro Cys IleAsp Pro Gly Ser Gln Ser Pro 210 215 220 Ser Gly Ile Gln Ala Glu Asn MetVal Ser Pro Gly Leu Lys Phe Pro 225 230 235 240 Thr Gln Asp Arg Ile SerLys Asp Ser Gln Pro Leu Gly Pro Leu Leu 245 250 255 Gln Asp Gly Asp ValAsp Glu Glu Cys Pro Ala Gln Ala Gln Met Pro 260 265 270 Pro Glu Leu GlnSer Asn Ser Ala Thr Gln Gln Asp Pro Asp Gly Ser 275 280 285 Gly Ala SerPhe Ser Ser Ser Ala Arg Gly Thr Gln Pro His Gly Tyr 290 295 300 Leu AlaLys Lys Leu His Ser Pro Ser Asp Gln Cys Pro Pro Arg Ala 305 310 315 320Lys Thr Pro Glu Pro Gly Ala Gln Gln Ser Gly Phe Pro Thr Leu Ser 325 330335 Arg Ser Pro Pro Gly Pro Ala Gly Ser Ser Pro Lys Gln Gly Arg Arg 340345 350 Tyr Arg Cys Gly Glu Cys Gly Lys Ala Phe Leu Gln Leu Cys His Leu355 360 365 Lys Lys His Ala Phe Val His Thr Gly His Lys Pro Phe Leu CysThr 370 375 380 Glu Cys Gly Lys Ser Tyr Ser Ser Glu Glu Ser Phe Lys AlaHis Met 385 390 395 400 Leu Gly His Arg Gly Val Arg Pro Phe Pro Cys ProGln Cys Asp Lys 405 410 415 Ala Tyr Gly Thr Gln Arg Asp Leu Lys Glu HisGln Val Val His Ser 420 425 430 Gly Ala Arg Pro Phe Ala Cys Asp Gln CysGly Lys Ala Phe Ala Arg 435 440 445 Arg Pro Ser Leu Arg Leu His Arg LysThr His Gln Val Pro Ala Ala 450 455 460 Pro Ala Pro Cys Pro Cys Pro ValCys Gly Arg Pro Leu Ala Asn Gln 465 470 475 480 Gly Ser Leu Arg Asn HisMet Arg Leu His Thr Gly Glu Lys Pro Phe 485 490 495 Leu Cys Pro His CysGly Arg Ala Phe Arg Gln Arg Gly Asn Leu Arg 500 505 510 Gly His Leu ArgLeu His Thr Gly Glu Arg Pro Tyr Arg Cys Pro His 515 520 525 Cys Ala AspAla Phe Pro Gln Leu Pro Glu Leu Arg Arg His Leu Ile 530 535 540 Ser HisThr Gly Glu Ala His Leu Cys Pro Val Cys Gly Lys Ala Leu 545 550 555 560Arg Asp Pro His Thr Leu Arg Ala His Glu Arg Leu His Ser Gly Glu 565 570575 Arg Pro Phe Pro Cys Pro Gln Cys Gly Arg Ala Tyr Thr Leu Ala Thr 580585 590 Lys Leu Arg Arg His Leu Lys Ser His Leu Glu Asp Lys Pro Tyr Arg595 600 605 Cys Pro Thr Cys Gly Met Gly Tyr Thr Leu Pro Gln Ser Leu ArgArg 610 615 620 His Gln Leu Ser His Arg Pro Glu Ala Pro Cys Ser Pro ProSer Val 625 630 635 640 Pro Ser Ala Ala Ser Glu Pro Thr Val Val Leu LeuGln Ala Glu Pro 645 650 655 Gln Leu Leu Asp Thr His Arg Glu Glu Glu ValSer Pro Ala Arg Asp 660 665 670 Val Val Glu Val Thr Ile Ser Glu Ser GlnGlu Lys Cys Phe Val Val 675 680 685 Pro Glu Glu Pro Asp Ala Ala Pro SerLeu Val Leu Ile His Lys Asp 690 695 700 Met Gly Leu Gly Ala Trp Ala GluVal Val Glu Val Glu Met Gly Thr 705 710 715 720 19 1431 DNA Homo sapiensCDS (151)...(1185) 19 ctaagaaaca aaagaatttc aagataatta ggtggagcgggcgggctggc tgctgaggac 60 gcgccgcctg cgccttcctc cctgcgtgcc tcgccccgggcggcccgggg ctgccgcggt 120 gcgcgggtgc cgggccctgc cttgccggcc atg ggg gaaggg ggc gcc gcg gcg 174 Met Gly Glu Gly Gly Ala Ala Ala 1 5 gcg ctg gtggcg gcg gca gca gca gca gca gcg gca gcg gca gcg gtg 222 Ala Leu Val AlaAla Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Val 10 15 20 gtg gcc ggg cagcgg cgg cgg cgg cta ggg cgc agg gcg cgc tgc cat 270 Val Ala Gly Gln ArgArg Arg Arg Leu Gly Arg Arg Ala Arg Cys His 25 30 35 40 ggg cct ggc cgggct gca ggc ggg aag atg tcc aag ccc tgc gcg gtg 318 Gly Pro Gly Arg AlaAla Gly Gly Lys Met Ser Lys Pro Cys Ala Val 45 50 55 gag gcg gcg gcg gcggcg gtg gca gcg acg gcc ccg ggc ccg gag atg 366 Glu Ala Ala Ala Ala AlaVal Ala Ala Thr Ala Pro Gly Pro Glu Met 60 65 70 gtg gag cgg agg ggc ccgggg agg ccc cgc acc gac ggg gag aac gta 414 Val Glu Arg Arg Gly Pro GlyArg Pro Arg Thr Asp Gly Glu Asn Val 75 80 85 ttt acc ggg cag tca aag atctat tcc tac atg agc ccg aac aaa tgc 462 Phe Thr Gly Gln Ser Lys Ile TyrSer Tyr Met Ser Pro Asn Lys Cys 90 95 100 tct gga atg cgt ttc ccc cttcag gaa gag aac tca gtt aca cat cac 510 Ser Gly Met Arg Phe Pro Leu GlnGlu Glu Asn Ser Val Thr His His 105 110 115 120 gaa gtc aaa tgc cag gggaaa cca tta gct gga atc tac agg aaa cga 558 Glu Val Lys Cys Gln Gly LysPro Leu Ala Gly Ile Tyr Arg Lys Arg 125 130 135 gaa gag aaa aga aat gctggg aac gca gta cgg agc gcc atg aag tcc 606 Glu Glu Lys Arg Asn Ala GlyAsn Ala Val Arg Ser Ala Met Lys Ser 140 145 150 gag gaa cag aag atc aaagac gcc agg aga cgt ccc ctg aag gaa aaa 654 Glu Glu Gln Lys Ile Lys AspAla Arg Arg Arg Pro Leu Lys Glu Lys 155 160 165 cgc aac aga atc gca aacacg gat ttc tac cct gtc cga agg agc tcc 702 Arg Asn Arg Ile Ala Asn ThrAsp Phe Tyr Pro Val Arg Arg Ser Ser 170 175 180 agg aag agc aaa gcc gagctg cag tct gaa gaa agg aaa aga ata gat 750 Arg Lys Ser Lys Ala Glu LeuGln Ser Glu Glu Arg Lys Arg Ile Asp 185 190 195 200 gaa ttg att gaa agtggg aag gaa gaa gga atg aag atc gac ctc atc 798 Glu Leu Ile Glu Ser GlyLys Glu Glu Gly Met Lys Ile Asp Leu Ile 205 210 215 gat ggc aaa ggc aggggt gtg att gcc acc aag cag ttc tcc cgg ggt 846 Asp Gly Lys Gly Arg GlyVal Ile Ala Thr Lys Gln Phe Ser Arg Gly 220 225 230 gcc ttt gtg gtg gaatac cac ggg gac ctc atc gag atc acc gac gcc 894 Ala Phe Val Val Glu TyrHis Gly Asp Leu Ile Glu Ile Thr Asp Ala 235 240 245 aag aaa cgg gag gctctg tac gca cag gac cct tcc acg ggc tgc tac 942 Lys Lys Arg Glu Ala LeuTyr Ala Gln Asp Pro Ser Thr Gly Cys Tyr 250 255 260 atg tac tat ttt cagtat ctg agc aaa acc tac tgc gtg gat gca act 990 Met Tyr Tyr Phe Gln TyrLeu Ser Lys Thr Tyr Cys Val Asp Ala Thr 265 270 275 280 aga gag aca aatcgc cta gga aga ctg atc aat cac agc aaa cgt ggg 1038 Arg Glu Thr Asn ArgLeu Gly Arg Leu Ile Asn His Ser Lys Arg Gly 285 290 295 aac tgc caa accaaa ctg cac gac atc gac ggc gta cct cac ctc atc 1086 Asn Cys Gln Thr LysLeu His Asp Ile Asp Gly Val Pro His Leu Ile 300 305 310 ctc atc gcc tcccga gac atc gcg gct ggg gag gag ccc ctg tat gac 1134 Leu Ile Ala Ser ArgAsp Ile Ala Ala Gly Glu Glu Pro Leu Tyr Asp 315 320 325 tat ggg gac cgcagc aag gct tcc att gaa gcc cac cca tgg ctg aag 1182 Tyr Gly Asp Arg SerLys Ala Ser Ile Glu Ala His Pro Trp Leu Lys 330 335 340 cat taaccggtgggccccgcgcc ctccccgccc cactttccct tcttcaaagg 1235 His 345 acaaagtgccctcaaaggga attgaatttt tttttacaca cttaatctta gcggattact 1295 tcagatgtttttaaaaagta tattaagatg ccttttcact gtagtattta aatatctgtt 1355 acaggtttccaaggtggact tgaacagatg gccttatatt accaaaactt ttatattcta 1415 gttgtttttgtacttt 1431 20 345 PRT Homo sapiens 20 Met Gly Glu Gly Gly Ala Ala AlaAla Leu Val Ala Ala Ala Ala Ala 1 5 10 15 Ala Ala Ala Ala Ala Ala AlaVal Val Ala Gly Gln Arg Arg Arg Arg 20 25 30 Leu Gly Arg Arg Ala Arg CysHis Gly Pro Gly Arg Ala Ala Gly Gly 35 40 45 Lys Met Ser Lys Pro Cys AlaVal Glu Ala Ala Ala Ala Ala Val Ala 50 55 60 Ala Thr Ala Pro Gly Pro GluMet Val Glu Arg Arg Gly Pro Gly Arg 65 70 75 80 Pro Arg Thr Asp Gly GluAsn Val Phe Thr Gly Gln Ser Lys Ile Tyr 85 90 95 Ser Tyr Met Ser Pro AsnLys Cys Ser Gly Met Arg Phe Pro Leu Gln 100 105 110 Glu Glu Asn Ser ValThr His His Glu Val Lys Cys Gln Gly Lys Pro 115 120 125 Leu Ala Gly IleTyr Arg Lys Arg Glu Glu Lys Arg Asn Ala Gly Asn 130 135 140 Ala Val ArgSer Ala Met Lys Ser Glu Glu Gln Lys Ile Lys Asp Ala 145 150 155 160 ArgArg Arg Pro Leu Lys Glu Lys Arg Asn Arg Ile Ala Asn Thr Asp 165 170 175Phe Tyr Pro Val Arg Arg Ser Ser Arg Lys Ser Lys Ala Glu Leu Gln 180 185190 Ser Glu Glu Arg Lys Arg Ile Asp Glu Leu Ile Glu Ser Gly Lys Glu 195200 205 Glu Gly Met Lys Ile Asp Leu Ile Asp Gly Lys Gly Arg Gly Val Ile210 215 220 Ala Thr Lys Gln Phe Ser Arg Gly Ala Phe Val Val Glu Tyr HisGly 225 230 235 240 Asp Leu Ile Glu Ile Thr Asp Ala Lys Lys Arg Glu AlaLeu Tyr Ala 245 250 255 Gln Asp Pro Ser Thr Gly Cys Tyr Met Tyr Tyr PheGln Tyr Leu Ser 260 265 270 Lys Thr Tyr Cys Val Asp Ala Thr Arg Glu ThrAsn Arg Leu Gly Arg 275 280 285 Leu Ile Asn His Ser Lys Arg Gly Asn CysGln Thr Lys Leu His Asp 290 295 300 Ile Asp Gly Val Pro His Leu Ile LeuIle Ala Ser Arg Asp Ile Ala 305 310 315 320 Ala Gly Glu Glu Pro Leu TyrAsp Tyr Gly Asp Arg Ser Lys Ala Ser 325 330 335 Ile Glu Ala His Pro TrpLeu Lys His 340 345 21 26 DNA Artificial Sequence Primer 21 tgtccctgcacgcccggaag tagatg 26 22 22 DNA Artificial Sequence Primer 22 tgtgctggaacgccagcagg tt 22 23 23 DNA Artificial Sequence Primer 23 gggggtagacgccttggttc acg 23 24 21 DNA Artificial Sequence Primer 24 catcgcaggagcacgccaca c 21 25 967 DNA Homo sapiens 25 gtcttgagga ccatctctcccggcagcata ccgtgtggct tcacactgct ctgcctctct 60 gaacctcggt ttcttcatctataaaatggg aataagagta agccacctca atggactgtg 120 ggaggcttaa gtaaattgaagtgccatgca agtagctagc atgcagttgc agctcaatga 180 atattatgat ggccgcagatacgatggcta cagctggggc acccatttcg ggtcacaagg 240 tagggttcaa tgttgaagatggcagagcca attgcatccc tgatgatcgt ggagtgccgg 300 gcctgcctga gatgctcacctctcttcctt taccagagag agaaagacag aatgaccgag 360 aacatgaagg agtgcttggcccagaccaat gcagccgtgg gggatatggt gacggtggtg 420 aatccgagcc aggagtatggccagccctgc tctaggagac cggactcctc ggccatggaa 480 gttgagccca agaaactgaaagggaagcgc gacctcatcg tgcccaaaag cttccagcaa 540 gtggacttct ggttttgtgagtcctgccag gagtacttcg tggatgaatg cccaaaccat 600 ggccccccgg tgtttgtgtctgacacaccg gtgcccgtgg gcatcccaga ccgggcggcg 660 ctcaccatcc cacagggcatggaggtggtc aaggacacta gtggagagag tgacgtgcga 720 tgtgtaaacg aggtcatccccaagggccac atcttcggcc cctatgaggg gcagatctcc 780 acccaggaca aatcagctggcttcttctcc tggctgattg tggacaagaa caaccgctat 840 aagtccatag atggctcagacgagaccgaa gccaactgga tgaggtacgt ggtcatctcc 900 cgggaggaga gggagcagaacctgctggcg ttccagcaca gtgagcgcat ctacttccgg 960 gcgtgca 967 26 622 DNAHomo sapiens 26 gaagatagtg tgtggctgct tctggactca aggaggagga gagagattccgcgagccgac 60 accatgcgat ccaaggcgag ggcgaggaag ctagccaaaa gtgacggtgacgttgtaaat 120 aatatgtatg agcccaaccg ggacctgctg gccagccaca gcgcggaggacgaggccgag 180 gacagtgcca tgtcgcccat ccccgtgggg tcaccgcccc ccttccccaccagcgaggac 240 ttcaccccca aggagggctc gccgtacgag gcccctgtct acattcctgaagacattccg 300 atcccagcag acttcgagct ccgagagtcc tccatcccag gggctggcctgggggtctgg 360 gccaagagga agatggaagc cggggagagg ctgggcccct gcgtggtggtgccccgggcg 420 gcggcaaagg agacagactt cggatgggag caaatactga cggacgtggaagtgtcgccc 480 caggaaggct gcatcacaaa gatctccgaa gacctgggca gtgagaagttctgcgtggat 540 gcaaatcagg cgggggctgg cagctggctc aagtacatcc gtgtggcgtgctcctgcgat 600 gaccagaacc tcaccatgtg tc 622 27 114 PRT Homo sapiens 27Lys Thr Arg Ile Phe Val Trp Ala Thr Lys Pro Ile Leu Lys Gly Lys 1 5 1015 Lys Phe Gly Pro Glu Val Gly Asp Lys Lys Lys Arg Ser Gln Val Lys 20 2530 Asn Asn Val Tyr Met Trp Glu Val Tyr Tyr Pro Asn Leu Gly Trp Met 35 4045 Cys Ile Asp Ala Thr Asp Pro Glu Lys Gly Asn Trp Leu Arg Tyr Val 50 5560 Asn Trp Ala Cys Ser Gly Glu Glu Gln Asn Leu Phe Pro Leu Glu Ile 65 7075 80 Asn Arg Ala Ile Tyr Tyr Lys Thr Leu Lys Pro Ile Ala Pro Gly Glu 8590 95 Glu Leu Leu Val Trp Tyr Asn Gly Glu Asp Asn Pro Glu Ile Ala Ala100 105 110 Ala Ile 28 117 PRT Homo sapiens 28 Glu Glu Val Ile Gly ValMet Ser Lys Glu Tyr Ile Pro Lys Gly Thr 1 5 10 15 Arg Phe Gly Pro LeuIle Gly Glu Ile Tyr Thr Asn Asp Thr Val Pro 20 25 30 Lys Asn Ala Asn ArgLys Tyr Phe Trp Arg Ile Tyr Ser Arg Gly Glu 35 40 45 Leu His His Phe IleAsp Gly Phe Asn Glu Glu Lys Ser Asn Trp Met 50 55 60 Arg Tyr Val Asn ProAla His Ser Pro Arg Glu Gln Asn Leu Ala Ala 65 70 75 80 Cys Gln Asn GlyMet Asn Ile Tyr Phe Tyr Thr Ile Lys Pro Ile Pro 85 90 95 Ala Asn Gln GluLeu Leu Val Trp Tyr Cys Arg Asp Phe Ala Glu Arg 100 105 110 Leu His TyrPro Tyr 115 29 111 PRT Homo sapiens 29 Gly Ala Gly Leu Gly Ile Trp ThrLys Arg Lys Ile Glu Val Gly Glu 1 5 10 15 Lys Phe Gly Pro Tyr Val GlyGlu Gln Arg Ser Asn Leu Lys Asp Pro 20 25 30 Ser Tyr Gly Trp Glu Ile LeuAsp Glu Phe Tyr Asn Val Lys Phe Cys 35 40 45 Ile Asp Ala Ser Gln Pro AspVal Gly Ser Trp Leu Lys Tyr Ile Arg 50 55 60 Phe Ala Gly Cys Tyr Asp GlnHis Asn Leu Val Ala Cys Gln Ile Asn 65 70 75 80 Asp Gln Ile Phe Tyr ArgVal Val Ala Asp Ile Ala Pro Gly Glu Glu 85 90 95 Leu Leu Leu Phe Met LysSer Glu Asp Tyr Pro His Glu Thr Met 100 105 110 30 117 PRT Homo sapiens30 Ile His Gly Arg Gly Leu Phe Cys Lys Arg Asn Ile Asp Ala Gly Glu 1 510 15 Met Val Ile Glu Tyr Ala Gly Asn Val Ile Arg Ser Ile Gln Thr Asp 2025 30 Lys Arg Glu Lys Tyr Tyr Asp Ser Lys Gly Ile Gly Cys Tyr Met Phe 3540 45 Arg Ile Asp Asp Ser Glu Val Val Asp Ala Thr Met His Gly Asn Arg 5055 60 Ala Arg Phe Ile Asn His Ser Cys Glu Pro Asn Cys Tyr Ser Arg Val 6570 75 80 Ile Asn Ile Asp Gly Gln Lys His Ile Val Ile Phe Ala Met Arg Lys85 90 95 Ile Tyr Arg Gly Glu Glu Leu Thr Tyr Asp Tyr Lys Phe Pro Ile Glu100 105 110 Asp Ala Ser Asn Lys 115 31 119 PRT Homo sapiens 31 Ile HisAsn Trp Gly Leu Tyr Ala Leu Asp Ser Ile Ala Ala Lys Glu 1 5 10 15 MetIle Ile Glu Tyr Val Gly Glu Arg Ile Arg Gln Pro Val Ala Glu 20 25 30 MetArg Glu Lys Arg Tyr Leu Lys Asn Gly Ile Gly Ser Ser Tyr Leu 35 40 45 PheArg Val Asp Glu Asn Thr Val Ile Asp Ala Thr Lys Lys Gly Gly 50 55 60 IleAla Arg Phe Ile Asn His Cys Cys Asp Pro Asn Cys Thr Ala Lys 65 70 75 80Ile Ile Lys Val Gly Gly Arg Arg Arg Ile Val Ile Tyr Ala Leu Arg 85 90 95Asp Ile Ala Ala Ser Glu Glu Leu Thr Tyr Asp Tyr Lys Phe Glu Arg 100 105110 Glu Lys Asp Asp Glu Glu Arg 115 32 89 PRT Homo sapiens 32 Gly SerGly Trp Gly Val Arg Ala Ala Thr Ala Leu Arg Lys Gly Glu 1 5 10 15 PheVal Cys Glu Tyr Ile Glu Glu Ile Ile Thr Ser Asp Glu Ala Asn 20 25 30 GluArg Gly Lys Ala Tyr Asp Asp Asn Gly Arg Thr Tyr Leu Phe Asp 35 40 45 LeuAsp Tyr Asn Thr Ala Gln Asp Ser Glu Tyr Thr Ile Asp Ala Ala 50 55 60 AsnTyr Gly Asn Ile Ser His Phe Ile Asn His Phe Asp Tyr Ile Arg 65 70 75 80Ala Asp Asn Glu Asp Val Pro Tyr Glu 85 33 118 PRT Homo sapiens 33 AspLys Gly Trp Gly Val Arg Thr Lys Leu Pro Ile Ala Lys Gly Thr 1 5 10 15Tyr Ile Leu Glu Tyr Val Gly Glu Val Val Thr Glu Lys Glu Phe Lys 20 25 30Gln Arg Met Ala Ser Ile Tyr Leu Asn Asp Thr His His Tyr Cys Leu 35 40 45His Leu Asp Gly Gly Leu Val Ile Asp Gly Gln Arg Met Gly Ser Asp 50 55 60Cys Arg Phe Val Asn His Ser Cys Glu Pro Asn Cys Glu Met Gln Lys 65 70 7580 Trp Ser Val Asn Gly Leu Ser Arg Met Val Leu Phe Ala Lys Arg Ala 85 9095 Ile Glu Glu Gly Glu Glu Leu Thr Tyr Asp Tyr Asn Phe Ser Leu Phe 100105 110 Asn Pro Ser Glu Gly Gln 115

What is claimed is:
 1. An isolated nucleic acid molecule encoding aPFM/SET polypeptide, said PFM/SET polypeptide having at least about 80%identity with an amino acid sequence referenced as SEQ ID NO:2, 4, 6, 8,10, 12, 14, 16, 18 or
 20. 2. The isolated nucleic acid molecule of claim1, encoding a PFM/SET polypeptide having at least about 90% identitywith an amino acid sequence referenced as SEQ ID NO:2, 4, 6, 8, 10, 12,14, 16, 18 or
 20. 3. The isolated nucleic acid molecule of claim 1,encoding a PFM/SET polypeptide having at least about 95% identity withan amino acid sequence referenced as SEQ ID NO:2, 4, 6, 8, 10, 12, 14,16, 18 or
 20. 4. The isolated nucleic acid molecule of claim 1, encodinga PFM/SET polypeptide comprising an amino acid sequence referenced asSEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18 or
 20. 5. The isolated nucleicacid molecule of claim 1, encoding a PFM/SET polypeptide consisting ofan amino acid sequence referenced as SEQ ID NO:2, 4, 6, 8, 10, 12, 14,16, 18 or
 20. 6. The isolated nucleic acid molecule of claim 1, whereinsaid PFM/SET polypeptide is encoded by a nucleotide sequence comprisinga nucleotide sequence selected from the group consisting of SEQ IDNOS:1, 3, 5, 7, 9, 11, 13, 15, 17 and
 19. 7. The isolated nucleic acidmolecule of claim 6, wherein said PFM/SET polypeptide is encoded by anucleotide sequence selected from the group consisting of SEQ ID NOS:1,3, 5, 7, 9, 11, 13, 15, 17 and
 19. 8. An isolated nucleic acid molecule,comprising a nucleotide sequence encoding a functional fragment of aPFM/SET polypeptide, said fragment comprising a PR, SET, PRAZ, or PKZLdomain of a PFM/SET amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and
 20. 9. Avector, comprising the isolated nucleic acid molecule of claim
 1. 10.The vector of claim 8, wherein said isolated nucleic acid molecule isoperatively linked to a promoter of RNA transcription.
 11. A host cell,comprising the vector of claim
 10. 12. An isolated oligonucleotide,comprising at least 17 contiguous nucleotides of a nucleotide sequencereferenced as SEQ ID NO:1,3, 5, 7, 9, 11, 13, 15, 17 or 19, or thecomplement thereof.
 13. A primer pair for detecting a PFM/SET nucleicacid molecule, comprising two isolated oligonucleotides according toclaim
 12. 14. A method for detecting a PFM/SET nucleic acid molecule ina sample, comprising contacting said sample with the PFM/SET nucleicacid molecule of claim 1 under conditions that allow specifichybridization to PFM/SET nucleic acid, and detecting said specifichybridization.
 15. A method for detecting a PFM/SET nucleic acidmolecule in a sample, comprising contacting said sample with the primerpair of claim 13 under conditions that allow amplification of PFM/SETnucleic acid, and detecting amplified PFM/SET nucleic acid.
 16. A methodfor modulating cell growth, comprising introducing the vector of claim10 into a host cell, and expressing encoded PFM/SET polypeptide in anamount effective to modulate growth of said cell.
 17. A method forisolating a PFM/SET polypeptide, comprising growing the host cell ofclaim 11 under conditions appropriate for expression of encoded PFM/SETpolypeptide, and isolating said PFM/SET polypeptide.
 18. An isolatedPFM/SET polypeptide, comprising a PFM/SET amino acid sequence having atleast about 80% amino acid identity with an amino acid sequence selectedfrom the group consisting of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18and
 20. 19. The isolated PFM/SET polypeptide of claim 18, having atleast about 90% amino acid identity with a PFM/SET amino acid sequenceselected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14,16, 18 and
 20. 20. The isolated PFM/SET polypeptide of claim 18, havingat least about 95% amino acid identity with a PFM/SET amino acidsequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8,10, 12, 14, 16, 18 and
 20. 21. An isolated PFM/SET polypeptide,comprising a PFM/SET amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and
 20. 22. Theisolated PFM/SET polypeptide of claim 21, consisting of a PFM/SET aminoacid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6,8, 10, 12, 14, 16, 18 and
 20. 32. A functional fragment of a PFM/SETpolypeptide, said fragment comprising a PR, SET, PRAZ, or PKZL domain ofa PFM/SET amino acid sequence selected from the group consisting of SEQID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and
 20. 33. An isolatedimmunogenic PFM/SET peptide, comprising at least 8 contiguous aminoacids of an amino acid sequence selected from the group consisting ofSEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and
 20. 34. An antibody, orantigen binding fragment thereof, which specifically binds to a PFM/SETpolypeptide comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 and
 20. 35. Amethod for detecting PFM/SET polypeptide in a sample, comprisingcontacting said sample with the antibody of claim 34 under conditionsthat allow specific binding of said antibody to PFM/SET polypeptide, anddetecting specifically bound antibody.